Boronic Acid Inhibitors of HIV Protease

ABSTRACT

Protease inhibitors, particularly aspartyl protease inhibitors, and more particularly HIV protease inhibitors which are boronated to enhance activity or to enhance entry into cells. Compounds, prodrugs and salts thereof of this invention contain phenylboronate groups, in particular p-B(OH) 2 -phenyl groups, benzoxaborole groups or borono-pyridyl groups or analogous groups in which the boronate group is protected. Methods for treating AIDS and ARC as well as providing a method for treating or preventing HIV infection

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/927,390, filed Oct. 29, 2015, which claims the benefit of andpriority to U.S. provisional application 62/072,367, filed Oct. 29,2014, both of which are incorporated by reference herein in itsentirety.

STATEMENT REGARDING GOVERNMENT FUNDING

This invention was made with government support under GM044783 awardedby the National Institutes of Health. The government has certain rightsin the invention.

BACKGROUND OF THE INVENTION

Acquired immunodeficiency syndrome (AIDS), characterized by thedestruction of the immune system, particularly of CD4 T-cells andsusceptibility to opportunistic infections, and its precursorAIDS-related complex (“ARC”), are the result of infection by the HIV(human immunodeficiency) retrovirus. HIV strains include HIV type 1(HIV-1) and HIV type 2 (HIV type 2). Retrovirus replication involvespost-translation processing of precursor polypeptides by a virallyencoded protease to produce mature viral proteins, viral assembly andthe generation of infective virus. Inactivation of the viral protease(HIV protease) can result in the production of non-infectious virus.Inhibition of HIV protease provides a method for treatment of AIDS andARC as well as providing a method for treating or preventing HIVinfection.

Several HIV protease inhibitors are presently approved for clinical usein the treatment of AIDS and HIV infection, including indinavir (seeU.S. Pat. No. 5,413,999), saquinavir (U.S. Pat. No. 5,196,438),ritonavir (U.S. Pat. No. 5,484,801), nelfinnavir (U.S. Pat. No.5,484,926), lopinavir (U.S. Pat. No. 5,914,332), atazanavir (U.S. Pat.No. 5,849,911), amprenavir (U.S. Pat. No. 5,585,397), darunavir (U.S.Pat. No. 6,248,775) and tipranavir (U.S. Pat. No. 5,852,195). Tipranaviris a non-peptide protease inhibitor, the other listed protease inhibitorare peptide-derived protease inhibitors. Protease inhibitors arecurrently administered in combination with at least one and typically atleast two other HIV antiviral agents, for example, nucleoside reversetranscriptase inhibitors such as zidovudine (AZT) and lamivudine (3TC)and/or non-nucleoside reverse transcriptase inhibitors, such asefavirenz and nevirapine. Combinations of the HIV protease inhibitorsmay be administered together, such as the combination of lopinavir andritonavir. Ritnovir can be administered with other HIV proteaseinhibitors as a booster. Fosamprenavir (fosamprenavir calcium), is apro-drug of the HIV protease inhibitor and antiretroviral drugamprenavir. Each of the above-listed U.S. patents is incorporated byreference herein in its entirety, for description of methods oftreatment and prevention of AIDs and HIV infection employing HIVprotease inhibitors, dosage forms for such treatment, drug combinationswith HIV protease inhibitors for such treatment, and administration ofHIV protease inhibitors alone or in combinations with otherantiretroviral drugs.

Of the listed approved HIV protease inhibitors amprenavir,fosamprenavir, darunavir and tipranavir contain sulfonamide structures.Additional HIV protease inhibitors include β-amino acidhydroxyethylamino sulfonamides, α-amino and β-amino acidhydroxyethylamino sulfonamides, lysine sulfonamides, among others. Thepresent invention relates to new sulfonamide derivatives which exhibitHIV protease inhibition, antiretroviral activity and which are usefulfor the treatment of AIDS and HIV infection.

The following patent documents provide description of HIV proteaseinhibitors having sulfonamide groups:

U.S. Pat. Nos. 5,585,397; 5,585,397; 5,744,481; 5,786,483; 5,843,946;5,852,195; 5,852,195; 5,856,353; 5,968,942; 6,060,476; 6,169,181;6,248,775; 6,248,775; 6,372,778; 6,417,387; 6,436,989; 6,472,407;6,500,832; 6,646,010; 6,924,286; 7,608,632; 7,981,929; or U.S. publishedapplication 20100093811. Each of these patents or published applicationsdescribe structures of HIV protease inhibitors and prodrugs thereofwhich contain at least on sulfonamide group (—NR—SO₂—Ar/Het) where thearyl of heteroaryl group can be replaced generally with a boronated arylgroup, a boronated heteroaryl group, an aryl group having a protectedboronate group, or a heteroary group having a protected boronate group.More specifically, the aryl or heteroaryl groups of such HIV proteaseinhibitor sulfonamides can be replaced with a phenylboronate group, abenzoxaborole group, a borono-pyridyl group or derivative groups thereofwhere the boronate is protected as described in the present invention.Each of these patents is incorporated by reference herein in itsentirety such description of the structures of HIV protease inhibitorsand prodrugs thereof and of methods of preparation of such compounds anduse of such compounds.

The use of HIV protease inhibitors has been impeded by difficulties withformulation (e.g., poor aqueous solubility), extensive metabolism,adverse effects in some patients, and the development of resistance toprotease inhibitors. There is in general a need for new HIV proteaseswith improved properties for formulation, increased in vivo half-lifeand to overcome resistance. Additionally, there is a need in the art forHIV protease inhibitors exhibiting enhanced levels of inhibition whichwill provide for lower effective dosage amounts.

SUMMARY OF THE INVENTION

The invention relates to protease inhibitors, particularly aspartylprotease inhibitors, and more particularly to those which inhibit HIVprotease. The invention provides compounds and certain prodrugs thereofand salts thereof which function as aspartyl protease inhibitors and HIVprotease inhibitors.

The compounds, prodrugs and salts thereof of this invention containphenylboronate groups, in particular p-B(OH)₂-phenyl groups,benzoxaborole groups or borono-pyridyl groups or analogous groups inwhich the boronate group is protected. More specifically, the phenylboronate, benzoxaborole groups or borono-pyridyl groups or analogousgroups in which the boronate group is protected replace certain aryl orheteroaryl groups of art-known sulfonamide HIV protease inhibitors andthe resulting phenyl boronates, benzoxaboroles, or borono-pyridyl groupsexhibit enhanced inhibition of HIV protease.

HIV protease inhibitors which are known in the art can be described bythe formula:

G-NR—SO₂—Ar/Het

where G, and R are various organic groups of known protease inhibitor,particularly known HIV inhibitors, which will be described in moredetail below in the detailed description and which are exemplifiedherein. Various structures for the G group are found in formulas I, Ia,II, IIA, III, IIIA, IV, IVA, V, VI, VII, Viii, X, XI, XXI, XXII, XXVI,XXVII, XXXI, XXXIII, XLI, XLIII, XXXVI, XXXVIII, L, LII, LV, LVII, LVIV,LVV, MM, M, MI, or MVI. In specific embodiments, R is C₁-C₄ alkyl orC₁-C₄ alkyl substituted with a C₃-C₇ cycloalkyl group, Ar is an arylgroup (e.g., optionally substituted phenyl) and Het is a heteroarylgroup (e.g., optionally substituted pyridyl). Replacement of Ar or Hetof such HIV inhibitors with a boronated aryl or boronated heteroarylgroup results in significant enhancement of inhibition of HIV protease.In a specific embodiment, replacement of Ar or Het with phenyl boronate,benzoxaborole, or borono-pyridyl group results in significantenhancement of inhibition of HIV protease. In a specific embodiment, theboronate group of the boronated aryl or boronated heteroaryl is itselfprotected with a boronate protecting group and more particularly with aprotecting group that is enzymatically removed in vivo. In a specificembodiment, the boronate protecting group is removed by an esterasefound in mammalian cells and more particularly in human cells. In suchan embodiment, the boronate protecting group is removed in vivo afteradministration. Protease inhibitors in which the aryl or heteroarylgroup of the sulfonamide protease inhibitor are replaced with aboronated aryl or hereteroaryl group, respectively, and in which theboronate group therein is protected can function as prodrug where theprotecting group is removed in vivo after administration.

The invention is directed to certain phenyl boronate compounds, certainprodrugs thereof and salts thereof. In specific embodiments, thecompounds, prodrugs and salts are useful for inhibition of aspartylproteases, particularly HIV aspartyl proteases. The phenylboronatecompounds, prodrugs and salts thereof of the invention are useful forthe treatment and prevention of HIV invention and AIDS.

The invention is directed to certain benzoxaborole compounds, certainprodrugs thereof and salts thereof. In specific embodiments, thecompounds, prodrugs and salts of the invention are useful for inhibitionof aspartyl proteases, particularly HIV aspartyl proteases. Thebenzoxaborole compounds, prodrugs and salts thereof of the invention areuseful for the treatment and prevention of HIV invention and AIDS.

The invention is directed to certain borono-pyridine compounds, certainprodrugs thereof and salts thereof. In specific embodiments, thecompounds, prodrugs and salts of the invention are useful for inhibitionof aspartyl proteases, particularly HIV aspartyl proteases. Theborono-pyridine compounds, prodrugs and salts thereof of the inventionare useful for the treatment and prevention of HIV invention and AIDS.

The invention is directed to pharmaceutically acceptable compositionswhich comprise a therapeutically effective amount of one or more of thephenyl boronates, benzoxaboroles, borono-pyridines or boronate protectedderivatives thereof of this invention and a pharmaceutically acceptablecarrier. The invention is directed to pharmaceutically acceptablecompositions which comprise a therapeutically effective amount of one ormore of the phenyl boronates, benzoxaboroles, borono-pyridines orboronate proteted derivatives thereof of this invention in apharmaceutically acceptable dosage form.

The invention is further directed to methods of treating mammals,particularly humans, with the compounds, prodrugs, and salts thereof andpharmaceutical compositions thereof of the invention.

The invention is additionally directed to a method for making animproved protease inhibitor wherein the protease inhibitor is of theformula:

G-NR—SO₂—Ar,

containing a aryl or heteroaryl group,which comprises the step of replacing the aryl or heteroaryl group ofthe protease inhibitor with a boronated aryl or boronated heteroarylgroup, wherein the boronate group in the boronated aryl or boronatedheteroaryl group is optionally protected with boronate protecting group.In specific embodiments, the protease inhibitor is an aspartyl proteaseinhibitor. In more particular embodiments, the protease inhibitor is anHIV protease inhibitor. In specific embodiments, the aryl is replacedwith phenyl boronate or benzoxaborole. In specific embodiments, theheteroaryl group is replaced with a borono-pyridine. In specificembodiments, the boronated aryl or boronated heteroaryl group contains aprotected boronate group. In specific embodiments, the boronateprotecting group is removed or is removable by an enzymatic reaction invivo, for example in mammalian cell or more particularly in human cells.In more specific embodiments, the boronate protecting group is removableby an esterase found in mammalian cells and more particularly in humancells. The term “replacement” is used herein with respect to theformulas of the group that is to be replaced and that of the boronatedaryl or heteroaryl group that will be in the resulting compound.Replacement is achieved by chemical conversion of the existing group tobe replaced or more typically by synthesis of the compound having theboronated aryl or heteroaryl group. This synthesis can be accomplishedin a variety of ways, for example, by choice of appropriate boronatedstarting materials or by boronation at an intermediate stage in thesynthesis.

Other aspects and embodiments of the invention will be apparent to oneof ordinary skill in the art on review of the detailed description, andexamples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-B are graphs showing the inhibition of the enzymatic activityof HIV-1 protease by (A) amprenavir and (B) darunavir, and the boronatedcognates B-amprenavir 6 and B-darunavir 9.

FIG. 2 is a scheme comparing the relative inhibition of the enzymaticactivity of HIV-1 protease by amprenavir, darunavir, and the boronatedcognates B-amprenavir 6 and B-darunavir 9. The boronated-cognatesexhibit more than a 10-fold enhancement in inhibition compared to theirnon-boronated cognate compounds.

FIG. 3 is a graph illustrating the inhibition of HIV cytopathic toxicityby B-darunavir.

FIGS. 4A-4D list representative A groups for compounds of the inventionincluding A1-A53.

FIGS. 5A-5B list representative P1 groups for compounds of theinvention.

FIGS. 6A-6C list representative R21 and R7 groups for compounds of theinvention.

FIG. 7 is a chemical scheme for an exemplary method for the introductionof a benzoxaborole group into HIV protease inhibitors of this inventionwhich are sulfonamide.

FIG. 8 is a first chemical scheme for an exemplary method for boronationof HIV protease inhibitors which are sulfonamide where a heteroarylgroup is attached to the —SO₂— group, specifically where the heteroarylgroup is a pyridyl.

FIG. 9 is a second chemical scheme for an exemplary method forboronation of HIV protease inhibitors which are sulfonamide where aheteroaryl group is attached to the —SO₂— group, specifically where theheteroaryl group is a pyridyl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to protease inhibitors, particularly HIVprotease inhibitors, having an aryl or heteroaryl sulfonamide group,wherein the aryl or heteroaryl group is a boronated aryl or boronatedheteroaryl group, e.g., a phenyl boronate group, a benzoxaborole groupor a borono pyridyl group. The inventors have found that suchsubstitution on known sulfonamide HIV protease inhibitors does notdetrimentally affect activity, but rather results in enhancedinhibition. In addition, the boronate group of the boronated aryl orboronated heteroaryl group is optionally protected with a boronateprotecting group that is removable in vivo to provide an exemplary HIVprotease inhibitor prodrug.

The inventors have determined that boronation on an aryl or heteroarylgroup of a sulfonamide protease inhibitor unexpectedly enhances thatactivity. Without wishing to be bound by any particular theory theinventors currently believe that the presence of phenyl boronate orboronated pyridyl groups, with a —B(OH)₂ group, or a benzoxaborolegroup, with a:

moiety, in the sulfonamide protease inhibitors of this invention asdescribed herein enhances binding of the inhibitor to the protease. Thisenhanced activity has been specifically demonstrated in sulfonamide HIVprotease inhibitors.

The term phenyl boronate group (which may also be called a phenylboronic acid group or a borono-phenyl group) refers to a phenyl groupcarrying a —B(OH)₂ group. The phenyl boronate group is formally amonovalent radical where a ring hydrogen is formally removed to form theradical. The phenyl boronate groups of this invention are not furthersubstituted with non-hydrogen groups on the ring. When the group is notfurther substituted with non-hydrogen groups, there are three isomers ofthe group dependent upon the ring carbon through which the group isbonded into the compounds therein. Numbering the carbons of the phenylring where the carbon carrying B is carbon 1, the isomers can be named2-phenyl boronate, and 3-phenyl boronate. The phenyl boronate groupgenerically has the formula:

where the position of the boronate group with respect to the carbonbonded to the rest of the inhibitor can vary. Compounds of the inventioncan be any of the positional isomers of the phenyl boronate group. Thepreferred phenyl boronate group is the 3-phenyl boronate group in whichthe —B(OH)₂ group is para to the site of the group's bonding, i.e., parato the carbon through which the group is bonded:

The term benzoxaborole group refers to a phenyl boronate group that issubstituted with a —CH₂—CH₂—OH group on the ring carbon next to (orthoto) the —B(OH)₂ group, wherein a five member ring fused to the phenylring is formed with loss of water. The benzoxaborole group is amonovalent radical formally formed by removal of a hydrogen from thephenyl ring. The benzoxaborole group generically has the formula:

where the position of the carbon bonded to boron with respect to thecarbon bonded to the rest of the inhibitor can vary. The benzoxaborolegroups of this invention are not further substituted with non-hydrogengroups on the ring. When the group is not further substituted withnon-hydrogen groups, there are four isomers of the group dependent uponthe ring carbon through which the group is bonded into the compoundsherein. Numbering the carbons of the phenyl ring where the carboncarrying B is carbon 1, the isomers can be named 2-benzoxaborole(2-benzoxaborolyl), 3-benzoxaborole (3-benzoxaborolyl), 4-benzoxaborole(4-benzoxaborolyl) and -5-benzoxaborole (5-benzoxaborolyl). Compounds ofthe invention can have any one of isomers of the benzoxaborole group.The preferred benzoxaborole groups are the 3-benzoxaborole (A) and the4-benzoxaborole (B) groups

The more preferred benzoxaborole group is 4-benzoxaborole, structure B.

Nitrogen-containing heteroaryl groups such as pyridyl groups can beboronated. Boronated pyridyl groups have the generic formula:

where the relative positions of the carbon bonded to the boronate, thecarbon bonded to the rest of the inhibitor and the ring nitrogen canvary. Boronated pyridyl groups include several isomers which will beapparent to one of ordinary skill in the art. In the present invention,preferred boronated heteroaryl groups are those where a —B(OH)₂ group isin the para-orientation from the site of its attachment in the proteaseinhibitor. For boronated pyridyl groups a preferred isomer is:5-borono-pyrid-2-yl:

An alternative boronated pyridyl group that can be used in the compoundsof the invention is the 6-borono-pyrid-2-yl:

Example 7 provides an exemplary synthesis of the boronated analogue oftipranavir, which contains the 5-borono-pyrid-2-yl group.

Boronate groups in the boronated aryl or boronated heteroaryl groups areoptionally protected with a boronate protecting group. A number of suchboronate protecting groups are known in the art. Of particular interestfor the applications herein are those boronate protecting groups thatcan be removed enzymatically by one or more enzymes found in vivo inmammalian cells and particularly in human cells. A particularly usefulboronate protecting reagent is N-methyliminodiacetic acid andderivatives thereof of formula:

where R_(N1) is hydrogen, alkyl (particularly C1-3 alkyl), cycloalkyl(particularly cyclohexyl), alkenyl (particularly C2-C4 alkenyl), aryl(particularly phenyl), heterocyclic groups (particularly heterocyclicgroups having a 5- or 6-member ring and 1 or 2 heteroatoms in the ringselected independently from N, O or S), heteroaryl groups (particularlyheteroaryl groups having a 5- or 6-member ring and 1 or 2 heteroatoms inthe ring selected independently from N, O or S), or an alkyl grouphaving 1-3 carbon atoms substituted with a cycloalkyl, aryl,heterocyclic, or heteroaryl group. In specific embodiments, R_(N1) ishydrogen.

In an embodiment, protected boronated aryl and heteroaryl groups areselected from those of formulas:

where the position of the protected boronate group with respect to thecarbon bonded to the rest of the inhibitor and with respect to a thering N (if present) can vary. The exemplified protected boronate groupis an N-substituted iminodiacetate boronate ester often shown asformula:

where R_(N1) is as defined above and more specifically is hydrogen.

A more specific protected boronated aryl group is that of the formula:

where R_(N1) is as defined above and more specifically is hydrogen.Other positional isomers of phenyl boronate can also be protected withthe N-substituted iminodiacetic acid.

More specific protected boronated heteroaryl groups are those of theformula:

where R_(N1) is as defined above and more specifically is hydrogen.Other positional isomers of borono-pyridyl can also be protected withthe N-substituted iminodiacetic acid.

U.S. Pat. Nos. 5,585,397, 5,856,353, 6,372,778, and 7,608,632 relate tosulfonamide inhibitors of aspartyl protease which are useful as HIVprotease inhibitors for the prevention and treatment of HIV infectionand AIDS. Each of these patents is incorporated by reference herein inits entirety for descriptions of the compounds and pharmaceuticallyacceptable derivatives thereof, for methods of synthesis of thesecompounds and derivatives, for pharmaceutical compositions comprisingthe compounds and derivatives, for pharmaceutical dosage forms of thecompounds and derivatives and for methods of treatment employing thesecompounds and derivatives and methods of administration of thesecompounds and derivatives to mammals and particularly to humans.Compounds of these patents include those of formula I:

where variables are defined therein and the listed patents areincorporated by reference herein to provide variable definitions. Morespecifically, x is 0 or 1, B if present is —N(R²)—C(R³)₂—CO—, where R²is among others hydrogen, C1-C3 alkyl or C1-C3 alkyl substituted with anaryl group (e.g., a phenyl group). More specifically D and D′ are amongothers independently selected from aryl, optionally substituted C1-C4alkyl, C1-C4 alkyl substituted with aryl or C3-C6 cycloalkyl, C2-C4alkenyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, where variables are asdefined in the listed patents. More specifically, A is among othershydrogen, A is selected among others from the group consisting of H;Het; and —CO-Het, and —CO—O-Het, where Het is selected among others fromthe group consisting of C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C6-C 10aryl; and 5-7 membered saturated or unsaturated heterocyclic groups,containing one or more heteroatoms selected from N, N(R²) O, S, SO orSO₂, wherein said heterocycle may optionally be benzofused. E as definedin the listed patents includes Het which is defined in these patents toinclude certain cycloalkyl, aryl and heterocyclic groups. The presentinvention provides compounds of the above formula as defined in thelisted patent where E is BBB which is a phenylboronate group, abenzoxaborole group, a borono-pyridyl group or boronate protectedderivatives thereof and in particular where BBB is selected from any oneof:

In a related embodiment, the invention provides compounds of the aboveformula as defined in the listed patent where E is:

These patents further provide compounds of formulas II, III and IV,respectively:

again where variables are as defined in the listed patents and morespecifically where A, D′ Het are as defined above, x is 1 or 0 and R³and R^(3′) is more specifically independently selected from the groupconsisting of among others, hydrogen, Het, C1-C6 alkyl, and C3-C6cycloalkyl. The present invention provides compounds andpharmaceutically acceptable derivatives (as defined therein) of each ofthese formulas where E is BBB which is a phenylboronate group, abenzoxaborole group, a boron-pyridyl group or a protected boronatederivative thereof and in particular where BBB is:

In a related embodiment, the invention provides compounds of the aboveformulas as defined in the listed patent where E is:

In a related embodiment, BBB is BBB1-BBB11 as defined above. In a morespecific embodiment, BBB is BBB9-BBB11.

Compounds of formulas I, II, III and IV above where E is BBB can beprepared, from starting materials and reagents that are commerciallyavailable or readily prepared by known methods, or routine adaptationsthereof, by one of ordinary skill in the art in view of methodsdescribed in U.S. Pat. Nos. 5,585,397, 5,856,353, 6,372,778, and7,608,632, in view of methods for introducing phenyl boronates,benzoxaboroles or boron-substituted pyridyl groups as described hereinand as are known in the art and in view of synthetic methods that arewell known in the art.

Compound herein containing a boronate protected aryl or a boronateprotected heteroaryl group can be prepared from starting materials andreagents that are commercially available or readily prepared by knownmethods, or routine adaptations thereof, by one of ordinary skill in theart, Compounds herein having a boronate group protected with anN-derivatized iminodiacetic acid (see formula above) can be preparedfrom starting materials and reagents that are commercially available orreadily prepared by known methods, or routine adaptations thereof, byone of ordinary skill in the art, in view of descriptions herein and inU.S. Pat. Nos. 8,318,983, 8,557,980 and 8,722,916 as well as inreferences 14-16. Each of these patent and non-patent references areincorporated by reference herein in its entirety for descriptions ofsynthesis of compounds having a boronate group protected with anN-derivatized iminodiacetic acid.

U.S. Pat. Nos. 5,843,946, 5,744,481, 5,786,483, 6,060,476, 6,472,407,6,500,832, relate to β-amino acid hydroxyethylamino sulfonamides,α-amino and β-amino acid hydroxyethylamino sulfonamides andpharmaceutically acceptable salts, prodrugs and esters thereof useful asretroviral protease inhibitors which are useful as HIV proteaseinhibitors for the prevention and treatment of HIV infection and AIDS.Each of these patents is incorporated by reference herein in itsentirety for descriptions of the compounds and pharmaceuticallyacceptable salts, prodrugs and/or esters thereof, for methods ofsynthesis of these compounds and derivatives, for pharmaceuticalcompositions comprising the compounds and pharmaceutically acceptablesalts, prodrugs and/or esters, for pharmaceutical dosage forms of thecompounds and derivatives and for methods of treatment employing thesecompounds, salts, prodrugs and esters and methods of administration ofthese compounds salts, prodrugs and esters to mammals and particularlyto humans. Compounds of these patents include those of formula IA:

where variables are as defined in the U.S. Pat. Nos. 5,843,946,5,744,481, and 5,786,483, which are each incorporated by referenceherein for the definitions of such variables. Compounds of these patentsinclude those in which x is 2 (e.g., sulfonamides) and where R⁴ is,among others, aryl and heteroaryl. Compounds of this patent includethose where Y is O or S, R⁶ is hydrogen and R³ is alkyl among others.

The present invention provides compounds and pharmaceutically acceptablederivatives (as defined therein) of each of these formulas where R⁴ isBBB which is a phenylboronate group, a benzoxaborole group, aborono-pyridyl group or a protected boronate derivative thereof. Inparticular BBB is BBB1-BBB11. In particular BBB is:

In a related embodiment, the invention provides compounds of the aboveformula as defined in the listed patent where BBB is:

In a related embodiment, the invention provides compounds of the aboveformula as defined in the listed patent where BBB is BBB9-BBB11.

Among the compounds described in U.S. Pat. Nos. 5,843,946, 5,744,481,5,786,483, 6,060,476, 6,472,407, 6,500,832 are those of formulasIIA-IVA:

therein,where variables are as defined in the listed U.S. patents andparticularly in U.S. Pat. Nos. 5,843,946, 5,744,481, and 5,786,483,which are each incorporated by reference herein for the definitions ofsuch variables. In these formulas, R⁴ is among others aryl andheteroaryl groups, R³ is among others alkyl groups. In these formulas:R is selected from hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylaminocarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, hetercaralkoxycarbonyl,heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, alkynyl, cycloalkyl,aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl, wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkyalkyl orwhere the aminocarbonyl and aminoalkanoyl radicals are disubstitutedsaid substituents along with the nitrogen atom to which they areattached form a heterocycloalkyl or heteroaryl group; andR′ represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkylradicals. wherein said substituents are selected from alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl groups or in the case of adisubstituted aminoalkyl moiety said substituents along with thenitrogen atom to which they are attached. form a heterocycloalkyl or aheteroaryl group orR and R′ together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radicals;R¹ and R^(1′) are independently selected fromhydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂, —CH₂CONHCH₃,—C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃), —C(CH₃)₂(S[O]₂CH₃),alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl groups, and amino acidside chains orR¹ and R^(1′) together with the carbon to which they are attachedpresent a cycloalkyl group; andR² is selected from alkyl, aryl, cycloalkyl, cycloalkylalkyl, andaralkyl groups (alkyl substituted with an aryl group, such as benzyl).

The present invention provides compounds and pharmaceutically acceptablederivatives (as defined therein) of each of these formulas where R⁴ isBBB which is a phenylboronate group, a benzoxaborole group, aborono-pyridyl group or a protected boronate derivative thereof. Inparticular BBB is BBB1-BBB11. In particular BBB is:

In related embodiments, BBB is:

In related embodiments, BBB is BBB9-BBB11.

Compounds of formulas I, II, III and IV, where R⁴ is BBB or a boronatedpyridyl group can be prepared, from starting materials and reagents thatare commercially available or readily prepared by known methods, orroutine adaptations thereof, by one of ordinary skill in the art in viewof methods described in U.S. Pat. Nos. 5,843,946, 5,744,481, 5,786,483,6,060,476, 6,472,407, 6,500,832 in view of methods for introducingphenyl boronates, benzoxaboroles and boronated pyridyl groups asdescribed herein and as are known in the art and in view of syntheticmethods that are well known in the art. Compounds herein having aboronate group protected with an N-derivatized iminodiacetic acid can beprepared from starting materials and reagents that are commerciallyavailable or readily prepared by known methods, or routine adaptationsthereof, by one of ordinary skill in the art, in view of descriptionsherein and in U.S. Pat. Nos. 8,318,983, 8,557,980 and 8,722,916 as wellas in references 14-16.

U.S. Pat. Nos. 5,968,942, 6,248,775, 6,646,010, 6,417,387 and 6,924,286relate to α-amino and β-amino acid hydroxyethylamino sulfonamides andpharmaceutically acceptable salts, prodrugs and esters thereof useful asretroviral protease inhibitors which are useful as HIV proteaseinhibitors for the prevention and treatment of HIV infection and AIDS.Each of these patents is incorporated by reference herein in itsentirety for descriptions of the compounds and pharmaceuticallyacceptable salts, prodrugs and/or esters thereof, for methods ofsynthesis of these compounds and derivatives, for pharmaceuticalcompositions comprising the compounds and pharmaceutically acceptablesalts, prodrugs and/or esters, for pharmaceutical dosage forms of thecompounds and derivatives and for methods of treatment employing thesecompounds, salts, prodrugs and esters and methods of administration ofthese compounds salts, prodrugs and esters to mammals and particularlyto humans. Compounds of these patents include those of the followingformula therein, herein designated formula V:

where variables are as defined in U.S. Pat. Nos. 5,968,942, 6,248,775,6,646,010, 6,417,387 and 6,924,286, which are each incorporated byreference herein for the definitions of such variable. Compounds ofthese patents include those in where R⁴ is, among others, aryl andheteroaryl. Specific variables in this structure are as defined above.

The present invention provides compounds and pharmaceutically acceptablederivatives (as defined therein) of this formula V, with variables asdefined in the listed patents, where R⁴ is BBB which is a phenylboronategroup, a benzoxaborole group, a borono-pyridyl group or a protectedboronate derivative thereof. In particular BBB is BBB1-BBB11. Inparticular, BBB is

In a related embodiment BBB is:

In another embodiment, BBB is BBB9-BBB11.

Compounds of the above formula as defined in U.S. Pat. Nos. 5,968,942,6,248,775, 6,646,010, 6,417,387 and 6,924,286, and named formula Vherein, except that R⁴ is BBB can be prepared, from starting materialsand reagents that are commercially available or readily prepared byknown methods, or routine adaptations thereof, by one of ordinary skillin the art in view of methods described in U.S. Pat. Nos. 5,968,942,6,248,775, 6,646,010, 6,417,387 and 6,924,286, in view of methods forintroducing phenyl boronates, benzoxaboroles, and boron-pyridyl groupsas described herein and as are known in the art and in view of syntheticmethods that are well known in the art.

U.S. Pat. Nos. 5,968,942, 6,248,775, 6,646,010, 6,417,387 and 6,924,286,also disclose compounds, salts, prodrugs and esters of the followingformula VI

where variables are as defined in the listed patents and particularly inthe claims of U.S. Pat. No. 6,248,775 which is incorporated by referenceherein for these variable definitions and again where R⁴ can, amongothers, be an aryl or heteroaryl group. In this formula:each of P¹ and P² are independently selected from hydrogen,alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, or mono- or disubstituted aminocarbonyl or mono- ordisubstituted aminoalkanoyl radical, wherein the substituents areselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl andheterocycloalkyalkyl radicals; or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;R² is an alkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkyl radical,which radicals are optionally substituted with a group selected fromalkyl and halogen radicals, nitro, cyano, CF₃, —OR⁹, —SR⁹, wherein R⁹ isa hydrogen or alkyl radical;R³ is a hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl or mono-or disubstituted aminoalkyl radical, wherein said substituents areselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals; or where the aminoalkyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached, form a heterocycloalkyl or a heteroaryl radical; andR⁴ is among others an aryl or heteroaryl group.

The present invention provides compounds and pharmaceutically acceptablederivatives (as defined therein) of this formula VI, with variables asdefined in the listed patents, where R⁴ is BBB which is a phenylboronategroup, a benzoxaborole group, a borono-pyridyl group or a protectedboronate derivative thereof. In particular BBB is BBB1-BBB11. Inparticular, BBB is

In a related embodiment, BBB is:

In another embodiment, BBB is BBB9-BBB11.

In specific embodiments the present invention provides compounds, salts,prodrugs and esters of formula VII

where P¹ is a heterocyclooxycarbonyl as defined in U.S. Pat. No.6,248,775, P² is hydrogen and R⁴ is where R⁴ is BBB which is aphenylboronate group, a benzoxaborole group, a borono-pyridyl group or aprotected boronate derivative thereof. In particular BBB is BBB1-BBB11.In particular, BBB is

In related embodiments, BBB is:

In other embodiments, BBB is BBB9-BBB11.

In more specific embodiments, P¹ is selected from a heterocyclocarbonyllisted in FIGS. 5-1 and 5-2, herein. In more specific embodiments, R³ inthe above formula is a C₁-C₄ alkyl or a C₁-C₄ alkyl substituted by aC₃-C₇-cycloalkyl group, or a phenyl group. In preferred embodiments, R³is butyl or isobutyl. In more specific embodiments, R² in the aboveformula is a C₁-C₄ alkyl substituted with a phenyl or a C₃-C₇cycloalkyl. In preferred embodiments, R² is —CH₂-phenyl.

Compounds of the above formulas where variables are as defined in U.S.Pat. Nos. 5,968,942, 6,248,775, 6,646,010, 6,417,387 and 6,924,286, andnamed formulas VI and VII herein, where R⁴ is BBB can be prepared, fromstarting materials and reagents that are commercially available orreadily prepared by known methods, or routine adaptations thereof, byone of ordinary skill in the art in view of methods described in U.S.Pat. Nos. 5,968,942, 6,248,775, 6,646,010, 6,417,387 and 6,924,286, inview of methods for introducing phenyl boronates, benzoxaboroles andborono-pyridyl groupsas described herein and as are known in the art andin view of synthetic methods that are well known in the art. Compoundsherein having a boronate group protected with an N-derivatizediminodiacetic acid (see formula above) can be prepared from startingmaterials and reagents that are commercially available or readilyprepared by known methods, or routine adaptations thereof, by one ofordinary skill in the art, in view of descriptions herein and in U.S.Pat. Nos. 8,318,983, 8,557,980 and 8,722,916 as well as in references14-16.

U.S. Pat. No. 6,436,989 relates to prodrugs of aspartyl proteaseinhibitors which are useful as prodrugs of HIV protease inhibitorsuseful for the prevention and treatment of HIV infection and AIDS. Thispatent is incorporated by reference herein in its entirety fordescriptions of the compounds and salts thereof, for methods ofsynthesis of these compounds and salts thereof, for pharmaceuticalcompositions comprising the compounds and salts, for pharmaceuticaldosage forms of the compounds and salts and for methods of treatmentemploying these compounds and salts and methods of administration ofthese compounds and salts to mammals and particularly to humans.Compounds and salts of these patents include those of formula VIII:

where variables are as defined therein and wherein U.S. Pat. No.6,436,989 is incorporated herein by reference for the definitions ofthese variables. In specific embodiments of the patent E is aryl orheteroaryl, among others. It is noted that certain exemplary R⁷ groupsare provided in FIG. 6-1, FIG. 6-2 and FIG. 6-3 herein. In specificembodiments, x is 0, D and D′ take values as listed above, x is 0 or 1and G if present is hydrogen, C₁-C₄ alkyl, or R⁷, A is —CO—O-Het, whereHet is a 5-7 membered saturated or unsaturated heterocyclic group,containing one or more heteroatoms selected from N, N(R²), O, S andS(O)_(n); heterocyclic group where n is 1 or 2 and R² is hydrogen or analkyl group. When G is not present, when x is 0, then the nitrogen towhich G is attached is bound directly to the R⁷ group on —OR⁷.

The present invention provides compounds and pharmaceutically acceptablederivatives (as defined therein) of formula I therein, where E is BBBBBB which is a phenylboronate group, a benzoxaborole group, aborono-pyridyl group or a protected boronate derivative thereof. Inparticular BBB is BBB1-BBB11. In particular, BBB is

In a related embodiment, BBB is:

In other embodiments, BBB is BBB9-BBB11.

Compounds of the above formulas I where variables are as defined in U.S.Pat. No. 6,436,989, except that E is BBB can be prepared, from startingmaterials and reagents that are commercially available or readilyprepared by known methods, or routine adaptations thereof, by one ofordinary skill in the art in view of methods described in U.S. Pat. No.6,436,989, in view of methods for introducing phenyl boronates,benzoxaboroles and boronated pyridyl groups as described herein and asare known in the art and in view of synthetic methods that are wellknown in the art.

In specific embodiments, the invention provides compounds, salts andprodrugs of formulas X or XI:

where BBB is a phenylboronate group, a benzoxaborole group, aborono-pyridyl group or a protected boronate derivative thereof,x is 0 or 1 to show the presence or absence of —XX—,—XX— when present is —O—, —CO—, —SO₂—, —CO—CO—, —O—CO—, —O—SO₂—,—NR₁₀—SO₂—, —NR₁₀—CO— or —NR₁₀—CO—CO—; where each R₁₀ is independentlyH, C1-C4 alkyl or C1-C4 alkyl substituted with C₃-C₇ cycloalkyl;R₂₀, R_(20A) and R_(20B) are independently selected from C₁-C₄ alkyl,C₃-C₆ cycloalkyl, C5-C6-cycloalkenyl, phenyl, C1-C4 alkyl substitutedwith one or more phenyl, or C3-C6 cycloalkyl groups, a C3-C6 cycloalkylgroup substituted with or fused to phenyl or a C5-C6 cycloalkyl groupsubstituted with or fused to a phenyl;R₂₁ is selected H; —PO₃(R₃)₂; or —PO₃R₃H or —PO₃H₂ or pharmaceuticallyacceptable salts thereof; or an acyl group (—CO—R₂₂), where R₂₂ isselected from C1-C4 alkyl, C2-C4 alkenyl, or C2-C10 alkyl wherein one ormore —CH₂— groups are replaced with —O—; or a C2-C10 alkyl wherein oneor more —CH₂— groups are replaced with —NH— or one or more —CH₃ groupsare replaced with —NR₂₃, where R₂₃ is H or a C1-C4 alkyl; andA is selected from H; Het; C6-C10 aryl; C3-C7 cycloalkyl; C5-C7cycloalkenyl; C1-C4 alkyl; C2-C4 alkenyl; C1-C4 alkyl substituted withone or more C1-C4 alkoxy, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, C6-C10aryl, or Het groups,wherein Het is selected from a 5-10 membered saturated, partiallysaturated or unsaturated cyclic group containing one or more heteroatomsor moieties selected from —N═; —N(R₂₄)—; —O—; —S—, —SO—; —SO₂—, or —CO—,where R₂₄ is selected from H, C1-C4 alkyl, C1-C4 alkyl substituted witha C3-C7 cycloalkyl group, or C1-C4 alkyl substituted with a C6-C10 arylgroup; andwherein each R₂₀, R₂₂, R₂₃, R₂₄, A or Het group is optionallysubstituted with one or more oxo, C₁-C₃-alkoxy, —OH, —C1-C3 alkyl,—CO—R₂₅, —N(R₂₅)₂, —CO₂R₂₅ (or when R₂₅ is H, pharmaceuticallyacceptable salts thereof), —NR₂₅—CO—R₂₅, —CO—N(R₂₅)₂, —(CH₂)_(r)—OH(where r is 1 or 2), —CN, —NO₂, halo or —CF₃, and R₂₅ is selected from Hor C₁-C₃ alkyl.

In particular embodiments, BBB is BBB1-BBB11. In particular embodiments,BBB is BBB9-BBB11. In particular embodiments BBB is

In specific embodiments of formula X, x is 1 and —XX— is present.Preferred —XX— are —O—, —CO—, —SO₂—, —O—CO—, and —NR₁₀—SO₂—. Morepreferred —XX— is —O—CO—. In specific embodiments, R₁₀ is H or —CH₃.Preferred R₁₀ are H. In specific embodiments, R_(20B) is H or C1-C4alkyl. Preferred R_(20B) is H. In specific embodiments, R_(20A) is C1-C4alkyl. In more preferred embodiments, R_(20A) is butyl and isobutyl. Inspecific embodiments, R₂₀ is C1-C4 alkyl substituted with an optionallysubstitutes phenyl ring. In more specific embodiments, R₂₀ is C1-C2alkyl substituted with unsubstituted phenyl.

In additional embodiments of formulas X and XI, A is selected fromunsubstituted Het, unsubstituted C1-C4 alkyl, unsubstituted C2-C4alkenyl, unsubstituted C6-C10 aryl or a C1-C4 alkyl group substitutedwith an unsubstituted C6-C10 aryl, or unsubstituted Het group.

In additional embodiments of formulas X and XI, Het is selected from a5-10 membered saturated cyclic group containing one or two oxygens asring members or a 5-10 membered saturated or unsaturated group which isoptionally substituted with one or two nitrogens as ring members.

In specific embodiment of formulas X and XI, A is a C1-C2 alkyl groupsubstituted with an optionally substituted pyridyl group or apharmaceutically acceptable salt thereof. In more specific embodiments,A is a C1-C2 alkyl group substituted with a pyrid-2-yl group, apyrid-3-yl group or a pyrid-4-yl group each of which is unsaturated.

In specific embodiments of formulas X or XI, A is selected from an Agroup provided in FIG. 4 (pages 1-4). More specifically A is one ofA1-A4, or one of A1-A14, or one of A1-A17, or one of A1-A27, or one ofA28-A30, or one of A31-A53. In FIG. 4 (pages 1-4), R is H or a C1-C4alkyl or a C1-C4 alkyl substituted with a C3-C7 cycloalkyl or a phenylgroup and is preferably H or —CH₃.

In specific embodiments, the invention provides compounds of formulasXXI-XXIV, XXI-N and XXII-N:

as well as boronate protected derivatives of formulas XXI, XXI-N, XXII,and XXII-N (see BBB9-BBB11, above) wherein:each R₂₀ is independently selected from C1-C4 alkyl, C3-C6 cycloalkyl,C5-C6-cycloalkenyl, phenyl, C1-C4 alkyl substituted with one or morephenyl, or C3-C6 cycloalkyl groups, a C3-C6 cycloalkyl group substitutedwith or fused to phenyl or a C5-C6 cycloalkyl group substituted with orfused to a phenyl;R₂₁ is selected H; —PO₃(R₃)₂; or —PO₃R₃H or —PO₃H₂ or pharmaceuticallyacceptable salts thereof; or an acyl group (—CO—R₂₂), where R₂₂ isselected from C1-C4 alkyl, C2-C4 alkenyl, or C2-C10 alkyl wherein one ormore —CH₂— groups are replaced with —O—; or a C2-C10 alkyl wherein oneor more —CH₂— groups are replaced with —NH— or one or more —CH₃ groupsare replaced with —NR₂₃, where R₂₃ is H or a C1-C4 alkyl; andA is selected from H; Het; C6-C10 aryl; C3-C7 cycloalkyl; C5-C7cycloalkenyl; C1-C4 alkyl; C2-C4 alkenyl; C1-C4 alkyl substituted withone or more C1-C4 alkoxy, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, C6-C10aryl, or a Het group, andHet is selected from a 5-10 membered saturated or unsaturated cyclicgroup containing one or more heteroatoms or moieties selected from —N═;—N(R₂₄)—; —O—; —S—, —SO—; —SO₂—, or —CO—, where R₂₄ is selected from H,C1-C3 alkyl, or C1-C3 alkyl substituted with a C6-C10 aryl group; andwherein each R₂₀, R₂₂, R₂₃, R₂₄, A or Het group is optionallysubstituted with one or more oxo, C1-C3-alkoxy, —OH, —C1-C3 alkyl,—CO—R₂₅, —N(R₂₅)₂, —CO₂R₂₅ (or when R₂₅ is H, pharmaceuticallyacceptable salts thereof), —NR₂₅—CO—R₂₅, —CO—N(R₂₅)₂, —(CH₂)_(r)—OH(where r is 1 or 2), —CN, —NO₂, halo or —CF₃, and R₂₅ is selected from Hor C1-C3 alkyl.

In more specific embodiments, each R₂₀, R₂₂, R₂₃, R₂₄, A or Het group isoptionally substituted with one of the above recited substituent groups.

In more specific embodiments, each R₂₀, R₂₂, R₂₃, R₂₄, A or Het group isoptionally substituted with one to three groups selected from oxo,—OCH₃, —OH, —C1-C3 alkyl, —COH, —COCH₃, —NH₂, —CO₂H or salts thereof,—NH—CO—H, —NH—CO—CH₃, —CO—NH₂, —CH₂CH₂—OH, —CN, —NO₂, halo or —CF₃. Inmore specific embodiments, each R₂₀, R₂₂, R₂₃, R₂₄, A or Het group isoptionally substituted with one to three groups selected from —OH, —COH,—COCH₃, —NH₂, —CO—NH₂, —CN, —NO₂, halo or —CF₃. In more specificembodiments, each R₂₀, R₂₂, R₂₃, R₂₄, A or Het group is optionallysubstituted with one to three groups selected from —OH, —NH₂, —NO₂, haloor —CF₃. In specific embodiments, the two instances of R₂₀ are differentgroups.

In more specific embodiments the compounds have formulas XXVI, XXVII,XXVIII, XXIX, XXVI-N or XXVII-N:

orboronate protected derivatives of compounds of formulas XXVI, XXVI-N,XXVII and XXVII-N (see BBB9-BBB11),where variables are defined for formulas XXI-XXIV and C representsoptional substitution of the indicated ring by one or more groupsselected from oxo, C1-C3-alkoxy, —OH, —C1-C3 alkyl, —CO—R₂₅, —N(R₂₅)₂,—CO₂R₂₅, —NR₂₅—CO—R₂₅, —CO—N(R₂₅)₂, —(CH₂)_(r)—OH, —CN, —NO₂, halo or—CF₃, and R₂₅ is selected from H or C1-C3 alkyl. In more specificembodiments, C represents substitution with one to three groups selectedfrom oxo, C1-C3-alkoxy, —OH, —C1-C3 alkyl, —CO—H, —CO—CH₃, —NH₂, —CO₂H,—NR₂₅—CO—R₂₅, —CO—NH₂, —(CH₂)—OH, —CN, —NO₂, halo or —CF₃, and R₂₅ isselected from H or C1-C3 alkyl. In more specific embodiments, Crepresents substitution with one of the listed groups. In more specificembodiments, C represents substitution with one to three groups selectedfrom —OH, —COH, —COCH₃, —NH₂, —CO—NH₂, —CN, —NO₂, halo or —CF₃. In morespecific embodiments, C represents substitution with one to three groupsselected from —OH, —NH₂, —NO₂, halo or —CF₃.

In a particular embodiment of formulas XXVI-XXIX, C is —OR_(C) whereR_(C) is selected from C1-C6 alkyl group, a C1-C6 alkyl substituted witha phenyl group, a C1-C6 group substituted with a C4-C7 cycloalkyl group,a C1-C6 alkyl group substituted with a 5-7 membered saturated, partiallysaturated or unsaturated heterocyclic group wherein the heterocyclicring has one or more heteroatom groups in the ring selected from —O—,—N═, —S—, —SO—, —SO₂—, or —N(R_(C5))— and/or wherein the heterocyclicring is substituted with one to four substituents selected from C1-C3alkyl, —CF₃, halo, C1-C3 alkoxy, or phenyl and R_(C5) is H or C1-C3alkyl. In a specific embodiment, R_(C) is a C1-C2 alkyl substituted withthe 5-7 member heterocyclic ring. In a more specific embodiment, R_(C)is a C1-C2 alkyl substituted with a 5-member heterocyclic ring as notedabove having —O—, —N═, —S—, or —N(R_(C5))— in the ring and beingoptionally substituted with one or more C1-C3 alkyl groups. In a morespecific embodiment —OR_(C) is:

In additional embodiments of formulas XXI-XXIX, A is selected fromunsubstituted Het, unsubstituted C1-C4 alkyl, unsubstituted C2-C4alkenyl, unsubstituted C6-C10 aryl or a C1-C4 alkyl group substitutedwith an unsubstituted C6-C10 aryl, or unsubstituted Het group.

In additional embodiments of formulas XX-XXIX, Het is selected from a5-10 membered saturated cyclic group containing one or two oxygens asring members or a 5-10 membered saturated or unsaturated group which isoptionally substituted with one or two nitrogens as ring members.

In specific embodiment of formulas XXI-XXIX, A is a C1-C2 alkyl groupsubstituted with an optionally substituted pyridyl group or apharmaceutically acceptable salt thereof. In more specific embodiments,A is a C1-C2 alkyl group substituted with a pyrid-2-yl group, apyrid-3-yl group or a pyrid-4-yl group each of which is unsaturated.

In specific embodiments of formulas XXI-XXIX, A is selected from an Agroup provided in FIG. 4 (pages 1-4). More specifically A is one ofA1-A4, or one of A1-A14, or one of A1-A17, or one of A1-A27, or one ofA28-A30, or one of A31-A53.

In specific embodiments of formulas XXI-XXIX, R₂₀ is a benzyl or anC1-C4 alkyl; R₂₁ is selected from H; —PO₃(R₃₁)₂; or —PO₃R₃₁H or —PO₃H₂or pharmaceutically acceptable salts thereof; and A is A₁ or A₂.

In more specific embodiments, the invention provides the compounds offormulas XXXI-XXXIV, XXXI-N and XXXIII-N:

orboronate protected derivatives of compounds of formulas XXXI, XXXI-N,XXXIII and XXXIII-N (see BBB9-BBB11).

In other embodiments, the invention provides prodrugs of formulas X, XI,XXI-XXIX, XXI-NXXIII-N, XXXI-XXXIV, XXXI-N, XXXIII-N, (above where H isreplaced with R²¹) and XLI-XLIV and XLI-N and XLIII-N:

orboronate protected derivatives of compounds of formulas XLI, XLI-N,XLIII and XLIII-N (see BBB9-BBB11),wherein R₂₁ is independently selected from groups:

wherein:each x is independently 0 or 1;Z is —O—, —S—, —N(R₂₇)— or, when M is absent Z is H;

Y is P or S; X is O or S;

wherein when Y is S, Z is not S;—R₂₆— is —C(R₂₇)₂—, —O—, or —N(R₂₇)—;each R₂₇ is independently H; C1-C4 alkyl; or a C1-C4 alkyl substitutedwith a 3-7 membered saturated, partially saturated or unsaturatedcarbocyclic group or a 5-7 membered saturated, partially saturated orunsaturated heterocyclic group containing one or more heteroatoms ormoieties selected from —O—, —N═, —S—, —SO—, SO₂— or —N(R₂₈)—, where R₂₈is H or a C1-C4 alkyl; and wherein each alkyl group, carbocyclic groupor heterocyclic group of R₂₇ is optionally substituted with one or moregroups selected from oxo, —OR₂₈, —C1-C4 alkyl, —N(R₂₈)₂, —N(R₂₈)—CO—R₂₈,—(CH₂)_(r)OH, (where r is 1-4), —CN, —CO₂R₂₈, —CO—N(R₂₈)₂, halo or —CF₃;each M is independently selected from H, cation having a +1 or +2 charge(e.g., Li⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺, Ba²⁺, —N(R₂₇)₄ ⁺), C1-C12 alkyl, C2-C12alkenyl, wherein 1 to 4 —CH₂— groups of the alkyl or alkenyl group,other than the —CH₂— that is bound to Z, is optionally replaced by aheteroatom group selected from —O—, —S—, —SO—, —SO₂—, or —N(R₂₇)—; or Mis R₃₀ which is selected from a 5-10 membered saturated, partiallysaturated or unsaturated carbocyclic or heterocyclic group wherein theheterocyclic groups contains one or more heteroatom groups selected from—O—, —S—, —SO—, —SO₂—, or —N(R₂₇)— and wherein the carbocyclic orheterocyclic groups are optionally substituted with one to foursubstituents selected from —OH, C1-C4 alkyl, C1-C4 alkoxy, or—O—CO—C1-C4 alkyl; and wherein any hydrogen(s) in said alkyl, alkenyl,carbocyclic or heterocyclic groups of M are optionally replaced with asubstituent selected from oxo, —OR₂₈, C1-C4 alkyl, C3-C7 cycloalkyl,C5-C6 cycloalkenyl, C6-C10 aryl, C5-C10 heterocyclic, —N(R₂₈)₂, —N(R₂₈)₃⁺, —(CH₂)r-OH, (where r is 1-4), —CN, —COz₂R₂₈, —CO—N(R₂₈)₂, —SO₂—N(R₂₈)₂, —N(R₂₈)—CO—R₂₈, —CO—R₂₈, —SO—R₂₈, —SO₂—R₂₈, —OCF₃, —SO—R₂₉,—SO₂—R₂₉, —N(R₂₈)—SO₂—R₂₈, halo, CF₃, or —NO₂;R₂₉ is selected from a 5-10 membered saturated, partially saturated orunsaturated carbocyclic or heterocyclic group wherein the heterocyclicgroup contains one or more heteroatom groups selected from —O—, —S—,—SO—, —SO₂—, or —N(R₂₇)— and wherein the carbocyclic or heterocyclicgroups are optionally substituted with one to four substituents selectedfrom —OH, C1-C4 alkyl, C1-C4 alkoxy, or —O—CO—C1-C4 alkyl; and whereinany hydrogen(s) in said alkyl, alkenyl, carbocyclic or heterocyclicgroups of M are optionally replaced with a substituent selected fromoxo, —OR₂₈, C1-C4 alkyl, —N(R₂₈)₂, —N(R₂₈)₃ ⁺, —(CH₂)_(r)—OH, (where ris 1-4), —CN, —CO₂—R₂₈, —CO—N(R₂₈)₂, —SO₂—N(R₂₈)₂, —N(R₂₈)—CO—R₂₈,—CO—R₂₈, —SO—R₂₈, —SO₂—R₂₈, —OCF₃, —N(R₂₈)—SO₂—R₂₈, halo, —CF₃, or —NO₂;andM′ is H, C1-C12-alkyl, C2-C12-alkenyl, or R₃₀; wherein 1 to 4 —CH₂—groups of the alkyl or alkenyl group are optionally replaced by aheteroatom group selected from —O—, —S—, —SO—, —SO₂—, or —N(R₂₇)—; andwherein any hydrogen(s) in said alkyl, alkenyl, or R₃₀ are optionallyreplaced with a substituent selected from oxo, —OR₂₈, C1-C4 alkyl,—N(R₂₈)₂, —N(R₂₈)₃ ⁺, —(CH₂)_(r)OH, (where r is 1-4), —CN, —CO₂R₂₈,—CO—N(R₂₈)₂, —SO₂—N(R₂₈)₂, —N(R₂₈)—CO—R₂₈, —CO—R₂₈, —SO—R₂₈, —SO₂—R₂₈,—OCF₃, —SO—R₂₉, —SO₂—R₂₉, —N(R₂₈)—SO₂(R₂₈), halo, —CF₃, or —NO₂.

Those of ordinary of skill in the art will understand that M or M′ inYY1 and YY2 have a covalent, a covalent/zwitterionic, or an ionicbonding relationship with R₂₆ or Z depending upon the selection of R₂₆,Z, M or M′. For example, when M or M′ is hydrogen, alkyl, alkenyl, orR₃₀, M or M′ is covalently bound to R₂₆ or Z. If M is a mono- ordivalent metal cation or other positively charged species (e.g., NH₄ ⁺),there is an ionic bonding interaction between M and Z and the resultingcompound is a salt. When x is 0 in (M)x (formula YY1), M is not presentand Z may be a charged species. In this case the other M in this formulamay be oppositely charged to produce a net zero charge on the molecule.Alternatively, the counter ion may located elsewhere in the molecule.

In specific embodiments, M is a pharmaceutically acceptable cation.

In specific embodiments, R₂₁ is selected from a group illustrates inFIG. 5 (pages 1-3).

In specific embodiments of formulas X, XI, XXI-XXIX and XLI-XLIV andboronate protected derivatives thereof, R₂₁ is selected from H;—PO₃(R₃₁)₂; or —PO₃R₃₁H or —PO₃H₂ or pharmaceutically acceptable saltsthereof; or an acyl group (—CO—R₂₂), where R₂₂ is selected from C1-C4alkyl, C2-C4 alkenyl, or C2-C10 alkyl wherein one or more —CH₂— groupsare replaced with —O—; or a C2-C10 alkyl wherein one or more —CH₂—groups are replaced with —NH— or one or more —CH₃ groups are replacedwith —NR₂₃, where R₂₃ is H or a C1-C4 alkyl and wherein R₃₁ is selectedfrom H, Het, C6-C10 aryl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl,or C5-C6 cycloalkenyl, wherein any group of R₃₁ is optionallysubstituted with one or more —OR₃₂, —CO—NH—R₃₂, —SO—N(R₃₂)₂,—SO₂—N(R₃₂)₂, Ht, —CN, —SR₃₂, —CO₂R₃₂, —NR₃₂—CO—R₃₂, where R₃₂ is H,C1-C4 alkyl or C1-C4 alkyl substituted with a 3-7 membered saturated,partially saturated or unsaturated carbocyclic group; or a 5-7 memberedsaturated, partially saturated or unsaturated heterocyclic groupcontaining one or more heteroatom groups selected from —O—, —N═, —S—,—SO—, —SO₂—, or —N(R₃₂)—, wherein the carbocyclic or heterocyclic groupis optionally substituted with one or more groups selected from oxo,OR₃₂, C1-C4 alkyl, —N(R₃₂)₂, —N(R₃₂)—CO—R₃₂, —(CH₂)r-OH (where r is1-4), —CN, —CO₂R₃₂, —CO—N(R₃₂)₂, halo or —CF₃.

In more specific embodiments of formulas X, XI, XXI-XXIX and XLI-XLIV,and boronate protected derivatives thereof, R₂₁ is selected from acylgroups, particularly —COH and acetyl groups. In more specificembodiments, R₂₁ is selected from acyl groups derived from amino acids(bonded through the carboxy), particularly those of L-amino acids,including seryl, lysyl, tyrosyl, valyl, histidyl, α-aspartyl,γ-glutamyl, β-aspartyl, β-glutamyl, pyridylalanyl, γ-alkyl-α-aspartyl(e.g., C1-C4-alkyl-O—CO—CH₂—CH(NH₂)—CO—).

In more specific embodiments of formulas X, XI, XXI-XXIX and XLI-XLIV,and boronate protected derivatives thereof, R₂₁ is selected from —SO₃₂—,and —CH₂—OSO₃ ²⁻ and pharmaceutically acceptable salts thereof,particularly sodium, potassium, calcium, magnesium and ammonium saltsthereof.

In more specific embodiments of formulas X, XI, XXI-XXIX and XLI-XLIV,and boronate protected derivatives thereof, R₂₁ is selected from H;—PO₃(R₃₁)₂; or —PO₃R₃₁H or —PO₃H₂ or pharmaceutically acceptable saltsthereof wherein R₃₁ is H, optionally substituted C1-C6 alkyl, oroptionally substituted C6-C10 aryl. In more specific embodiments, R₃₁ isH; C1-C6 alkyl optionally substituted with one or more, —C1-C4 alkoxy,—OH, —NH₂, or —N(C1-C4 alkyl); a C1-C4 alkyl optionally substituted witha phenyl group or a phenyl group wherein said phenyl groups areoptionally substituted with one or more —C1-C4 alkoxy, —OH, —NH₂, or—N(C1-C4 alkyl).

In more specific embodiments of formulas X, XI, XXI-XXIX and XLI-XLIV,and boronate protected derivatives thereof, R₂₁ is selected from —PO₃H₂,—PO₃H⁻, —PO₃ ²⁻, —CH₂—OPO₃H₂, —CH₂—OPO₃H⁻, —CH₂—OPO₃ ²⁻ andpharmaceutically acceptable salts thereof, including in particularsodium, potassium, calcium, magnesium and ammonium salts thereof.

The invention specifically provides prodrugs which are compounds orpharmaceutically acceptable salts of formulas XXXVI-XXXIX and XXXVI-Nand XXXVIII-N:

orboronate protected derivatives of compounds of formulas XXXVI, XXXVI-N,XXXVIII and XXXVIII-N(see BBB9-BBB11).

In specific embodiments of salts of formulas XXXVI-XXXIX and of boronateprotected derivatives of formulas XXXVI, XXXVI-N, XXXVIII and XXXVIII-Nare sodium, potassium, magnesium or calcium salts.

U.S. Pat. Nos. 5,852,195 and 6,169,181 describe HIV protease inhibitorshaving an aryl sulfonamide group. Each of these patents is incorporatedby reference herein in its entirety for the description therein of suchcompounds and salts thereof and methods of synthesizing such compounds.

Among the compounds in these patents are compounds of formulas therein:

wherein R³ is the moiety of formula VB or XB:

where R₅ and R₉ are, among other groups, an —NR₁₂—SO₂-phenyl group,where the other variables are as defined in U.S. Pat. Nos. 5,852,195 and6,169,181. The present invention includes compounds and salts thereof asdescribed in U.S. Pat. Nos. 5,852,195 and 6,169,181 wherein the arylgroup linked to —SO₂— in such R₅ and R₉ groups as described therein isreplaced with a phenyl boronate, benzoxaborole group, a borono-pyridylgroup, or an analogous boronate protected group, particularly as in R₃groups as defined therein which have formula V/X-boronate, V/Xbenzboronate and V/X borono-pyridyl:

where BB is:

orboronate protected derivatives of V/X-boronate or V/X-boronopyridyl,where R₄, R₇ and R₁₂ are as defined in U.S. Pat. Nos. 5,852,195 and6,169,181. In specific embodiments, the compounds of this invention havestructures IAA or IBB:

orstructure VIBB:

where variables other than R₃ are as defined in U.S. Pat. Nos. 5,852,195and 6,169,181. Compounds of the present invention include those offormulas I, IA, IB, II and VI as defined in U.S. Pat. Nos. 5,852,195 and6,169,181 where R₃ is the formula V/X-boronate, the formula V/Xbenzoxaborole, the formula V/X borono-pyridinyl above or protectedboronate derivatives thereof.

In specific embodiments of formulas I, IAA, IBB, IIBB and VIBB above R₂and R₆ are independently selected from C3-C5 alkyl; C2-C6 haloalkyl;C1-C12 alkyl substituted with halo, —N₃, phenyl, C3-C7 cycloalkyl, C5-C6cycloalkenyl, Het, —NH₂—SO₂—Het; phenyl, substituted with one or morehalo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, C5-C6cycloalkenyl, Het, or —NH₂—SO₂—Het; C3-C12 alkyl wherein one or more—CH₂— groups are replaced with —O— and/or one or more —CH₃ are replacedwith —OH; C2-C12 alkyl wherein one or more —CH₂— groups are replacedwith —NR₄₁— and/or one or more —CH₃ are replaced with —N(R₄₁)₂, whereR₄₁ is H or C1-C4 alkyl; C3-C12 alkyl wherein one or more —CH₂— groupsare replaced with —O— or —NR₄₁— and/or one or more —CH₃ are replacedwith —OH or —N(R₄₁)₂, where R₄₁ is H or C1-C4 alkyl; C2-C12 alkylwherein one or more —CH₂— groups are replaced with —CO— or —NR₄₁— and/orone or more —CH₃ are replaced with —N(R₄₁)₂, —OH, —COOH, or —SO₃H, whereR₄₁ is H or C1-C4 alkyl; or —Het-CO—NH—C1-C3-alkyl;

R₄/R₇ is C1-C4 alkyl; andR₁₂ is H or C1-C4 alkyl.

In preferred embodiments, R₂ and R₆ are different groups. In preferredembodiments, R₄/R₇ is ethyl, t-butyl or cyclopropyl. In preferredembodiments, R₁₂ is H. In preferred embodiments, the compound of thisinvention is a compound of formula VI as defined in U.S. Pat. Nos.5,852,195 and 6,169,181, with the exception that R₃ is the group offormula V/X-boronate, the group of formula V/X benzoxaborole, the groupof the formula of V/X-boronated pyridyl, or protected boronatederivatives thereof.

In specific embodiments, invention provides compounds of formula L, LI,LI-N, LII, LIII or LIII-N:

orboronate protected derivatives of compounds of formulas LI, LI-N, LIIIand LIII-N (see BBB9-BBB11),where, R₄₀ and R₄₅ are independently selected from C3-C5 alkyl; C2-C6haloalkyl; C1-C12 alkyl substituted with halo, —N₃, phenyl, C3-C7cycloalkyl, C5-C6 cycloalkenyl, Het, —NH₂—SO₂—Het; phenyl, substitutedwith one or more halo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl,C5-C6 cycloalkenyl, Het, or —NH₂—SO₂—Het; C3-C12 alkyl wherein one ormore —CH₂— groups are replaced with —O— and/or one or more —CH₃ arereplaced with —OH; C2-C12 alkyl wherein one or more —CH₂— groups arereplaced with —NR₄₁— and/or one or more —CH₃ are replaced with —N(R₄₁)₂,where R₄₁ is H or C1-C4 alkyl; C3-C12 alkyl wherein one or more —CH₂—groups are replaced with —O— or —NR₄₁— and/or one or more —CH₃ arereplaced with —OH or —N(R₄₁)₂, where R₄₁ is H or C1-C4 alkyl; C2-C12alkyl wherein one or more —CH₂— groups are replaced with —CO— or —NR₄₁—and/or one or more —CH₃ are replaced with —N(R₄₁)₂, —OH, —COOH, or—SO₃H, where R₄₁ is H or C1-C4 alkyl; or —Het-CO—NH—C1-C3-alkyl;R₅₀ is C1-C4 alkyl; andR₅₅ is H or C1-C4 alkyl.

In preferred embodiments, R₄₀ and R₄₅ are different groups. In preferredembodiments, R₅₀ is ethyl, t-butyl or cyclopropyl. In preferredembodiments, R₅₅ is H.

In preferred embodiments, R₄₀ and R₄₅ are independently selected fromR₄₂—(CH₂)n-CH(R₄₃)— where n is 0, 1 or 2; CH₃—[O(CH₂)₂]₂—CH₂—, C3-C5alkyl, phenyl-(CH₂)₂—, Het-SO₂NH—(CH₂)₂—, (HOCH₂)₃C—NH—CO—NH—(CH₂)₃—,(HO—CO)(NH₂)CH—(CH₂)₂—CO—NH—(CH₂)₃—, piperazin-1-yl-CO—NH—(CH₂)₃—,HO₃S—(CH₂)₂—N(CH₃)—CO—(CH₂)₆—CO—NH—(CH₂)₃—, cyclopropyl-(CH₂)₂—,F-phenyl-(CH₂)₂—, Het-SO₂NH-phenyl-, or CF₃—(CH₂)₂—, wherein R₄₂ isselected from phenyl, Het, cyclopropyl, CH₃—[O(CH₂)₂]₂—, Het-SO₂NH—,Br—, N₃—, or HO₃S(CH₂)₂—N(CH₃)—CO—(CH₂)₆—CO—NH—; and R₄₃ is selectedfrom ethyl, or —CH₂-cyclopropyl;

In more preferred embodiments, one of R₄₀ or R₄₅ is C3-C5 alkyl and theother is phenyl-(CH₂)₂—, cyclopropyl-(CH₂)₂—, F-phenyl-(CH₂)₂—,Het-SO₂NH-phenyl-, or CF₃—(CH₂)₂—.

In more preferred embodiments, R₄₅ is C3-C5 alkyl and R₄₀ isphenyl-(CH₂)₂—, cyclopropyl-(CH₂)₂—, F-phenyl-(CH₂)₂—, orHet-SO₂NH-phenyl-. In yet more preferred embodiments, R₄₅ is n-propyland R₄₀ is phenyl-(CH₂)₂—.

In specific embodiments of formulas L and LI, R₅₀ is ethyl, R₅₅ is H,R₄₅ is C3-C5 alkyl and R40 is C1-C2 alkyl substituted with phenyl. Inother specific embodiments of formulas L and LI, R₅₀ is ethyl, R₅₅ is H,R₄₅ is n-propyl and R₄₀ is —(CH₂)₂-phenyl.

Compounds of formulas I, IA, IB, II, VI, L and LI where R₃ is the groupof formula V/X-boronate, X/V benzoxaborole or X/V borono-pyridinyl canbe prepared, from starting materials and reagents that are commerciallyavailable or readily prepared by known methods, by one of ordinary skillin the art in view of methods described in U.S. Pat. Nos. 5,852,195 and6,169,181, in view of methods for introducing phenyl boronates,benzoxaboroles and borono-pyridyl as described herein and as are knownin the art and in view of synthetic methods that are well known in theart. Compounds herein having a boronate group protected with anN-derivatized iminodiacetic acid (see formula above) can be preparedfrom starting materials and reagents that are commercially available orreadily prepared by known methods, or routine adaptations thereof, byone of ordinary skill in the art, in view of descriptions herein and inU.S. Pat. Nos. 8,318,983, 8,557,980 and 8,722,916 as well as inreferences 14-16.

U.S. published application 20100093811, published Apr. 15, 2010,describes HIV protease inhibitors having an aryl sulfonamide group. Thispublished patent application describes compounds of formula LL andprovides definition of the variables of this formula. The patentapplication further describes the compounds and salts thereof andmethods of synthesizing such compounds and salts. This published patentapplication is incorporated by reference herein in its entirety forthese descriptions as well as for applications and pharmaceuticalcompositions containing these compounds and salts. The compounds thereindesignated lysine sulfonamides have formula (designated formula Itherein) and designated formula LL herein:

where the definitions of the formula variables are incorporated byreference herein from U.S. published application 20100093811.

In embodiments,

R¹ is C1-6 alkyl, C1-6 fluoroalkyl, C3-6 cycloalkyl, or C1-6 alkylsubstituted with C3-6 cycloalkyl;R² is CH(R^(J))—Z, and Z is OH, NH2, or OR^(P);R^(J) is H, C1-6 alkyl, C1-6 fluoroalkyl, or C1-6 alkyl substituted withC3-5 cycloalkyl;R^(P) is P(O)(OH)₂, P(O)(OM)₂, or C(O)R^(Q);M is an alkali metal or an alkaline earth metal;R^(Q) is C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkyl substituted with C3-6cycloalkyl, O—C1-6 alkyl, O—C1-6 alkyl substituted with O—C1-6 alkyl,O—C1-6 fluoroalkyl, C(O)O—C1-6 alkyl, C(O)—C1-6 alkylene-N(H)—C1-6alkyl, C(O)—C1-6 alkylene-N(—C1-6 alkyl)₂, C1-6 alkyl substituted withC(O)O—C1-6 alkyl, C1-6 alkyl substituted with C(O)OH, C1-6 alkylsubstituted with C(O)—C1-6 alkyl, N(H)—C1-6 alkyl, N(—C1-6 alkyl)₂, C1-6alkyl substituted with NH₂, N(H)—C1-6 alkyl, or N(—C1-6 alkyl)₂, AryA,C1-6 alkyl substituted with AryA, O—C1-6 alkyl substituted with AryA,HetA, C1-6 alkyl substituted with HetA, O—C1-6 alkyl substituted withHetA, HetB, or O-HetB;R³ is H, C1-6 alkyl, C1-6 fluoroalkyl, or C1-6 alkyl substituted withC3-6 cycloalkyl;R⁴ is H, C1-6 alkyl, C1-6 fluoroalkyl, or C1-6 alkyl substituted withC3-6 cycloalkyl;R⁵ is H, C1-6 alkyl, C1-6 fluoroalkyl, C1-6 alkyl substituted with OH,C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or C1-6 alkyl substitutedwith C3-6 cycloalkyl;R^(5A) is H or C1-6 alkyl;alternatively, R⁵ and R^(5A) together with the carbon atom to which theyare both attached form C3-6 cycloalkyl;

R⁶ is

wherein the asterisk (*) denotes the point of attachment to the rest ofthe compound;R^(6A) is H or C1-6 alkyl;alternatively, R⁶ and R^(6A) together with the carbon to which they areattached form a C3-6 cycloalkyl which is optionally substituted withphenyl, wherein the phenyl is optionally substituted with from 1 to 3X^(B).each X^(B) and each X^(C) are independently selected from the groupconsisting of:C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, OH, O—C1-6 alkyl, O—C1-6haloalkyl, O—C3-6 cycloalkyl, SH, S—C1-6 alkyl, S—C1-6 haloalkyl, S—C3-6cycloalkyl, halo, CN, NO₂, NH₂, N(H)—C1-6 alkyl, N(—C1-6 alkyl)₂,N(H)C(O)—C1-6 alkyl, N(H)CH(O), CH(O), C(O)—C1-6 alkyl, C(O)OH,C(O)O—C1-6 alkyl, SO₂H, SO₂—C1-6 alkyl; and C1-6 alkyl substituted with:C1-6 haloalkyl, OH, O—C1-6 alkyl, O—C1-6 halo alkyl, O—C3-6 cycloalkyl,SH, S—C1-6 alkyl, halo, CN, NO₂, NH₂, N(H)—C1-6 alkyl,N(—C1-6 alkyl)₂, C(O)—C1-6 alkyl, C(O)OH, C(O)O—C1-6 alkyl, or SO2-C1-6alkyl;

T is O, S, S(O), or SO₂;

m is an integer equal to 0, 1, 2, or 3;n is an integer equal to 0, 1, 2, or 3;R⁷ is H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkyl substituted withC3-6cycloalkyl, or C(O)—R^(K);R⁸ is H or C1-6 alkyl;R^(K) is: C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkyl substituted with C3-6cycloalkyl, O—C1-6 alkyl, O—C1-6 alkyl substituted with O—C1-6 alkyl,O—C1-6 fluoro alkyl, C(O)O—C1-6 alkyl, C1-6 alkyl substituted withC(O)O—C1-6 alkyl, C1-6 alkyl substituted with C(O)OH, C1-6 alkylsubstituted with C(O)—C1-6 alkyl, N(H)—C1-6 alkyl, N(—C1-6 alkyl)₂, C1-6alkyl substituted with NH₂, N(H)—C1-6 alkyl, or N(—C1-6alkyl)₂, AryA,C1-6 alkyl substituted with AryA, O—C1-6 alkyl substituted with AryA,HetA, C1-6 alkyl substituted with HetA, O—C1-6 alkyl substituted withHetA, HetB, O-HetB, or O—C1-6 alkyl substituted with HetB;each AryA is an aryl which is independently phenyl or naphthyl, whereinthe phenyl or naphthyl is optionally substituted with from 1 to 4 Y^(B)wherein each Y^(B) independently has the same definition as X^(B);each HetA is a heteroaryl which is independently (i) a 5- or 6-memberedheteroaromatic ring containing from 1 to 3 heteroatoms independentlyselected from N, O and S, or (ii) is a heterobicyclic ring selected fromquinolinyl, isoquinolinyl, and quinoxalinyl; wherein the heteroaromaticring (i) or the bicyclic ring (ii) is optionally substituted with from 1to 4 Y^(C) wherein each Y^(C) independently has the same definition asX^(B); andeach HetB is independently a 4- to 7-membered, saturated or unsaturated,non-aromatic heterocyclic ring containing at least one carbon atom andfrom 1 to 4 heteroatoms independently selected from N, O and S, whereeach S is optionally oxidized to S(O) or S(O)₂, and wherein thesaturated or unsaturated heterocyclic ring is optionally substitutedwith from 1 to 4 substituents each of which is independently halogen,CN, C1-6 alkyl, OH, oxo, O—C1-6 alkyl, C1-6 haloalkyl, O—C1-6 haloalkyl,C(O)NH₂, C(O)N(H)—C1-6 alkyl, C(O)N(—C1-6 alkyl)₂, C(O)H, C(O)—C1-6alkyl, CO₂H, CO₂—C1-6 alkyl, SO₂H, or SO₂—C1-6 alkyl.

The present invention includes compounds and salts thereof as describedtherein wherein the aryl group linked to —SO₂— is replaced with a phenylboronate, a benzoxaborole group or a borono-pyridyl group, or analogousboronate protected groups particularly as in formula LV, LVI, LVII andLVIII:

where BBN is defined above,

orboronate protected derivatives of compounds of formulas LVI, or LVII(see BBB9-BBB11),where BBN is as defined above,and other variables are defined as in U.S. published application20100093811 and in embodiments as described above. In specificembodiments R⁶ and R^(6A) are both phenyl groups.

In specific embodiments, R² is C1-C4 alkyl substituted with an —OH,—NH₂, —PO(OH)₂ or pharmaceutically acceptable salts thereof, or a—COR^(Q) group where R^(Q) is C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6alkyl substituted with C3-C6 cycloalkyl or phenyl. In other specificembodiments, R² is —CH(RJ)-Z where Z is —OH, —NH₂, —PO(OH)₂ orpharmaceutically acceptable salts thereof, or a —COR^(Q) group whereR^(Q) is C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkyl substituted withC3-C6 cycloalkyl or phenyl. In specific embodiments, R² is —CH₂—Z whereZ is —OH, —NH₂, —PO(OH)₂ or pharmaceutically acceptable salts thereof.In specific embodiments, R¹ is H or C1-C4 alkyl. In specificembodiments, R³, R⁴, R⁵ and R^(5A) are H or C1-C4 alkyl. In specificembodiments, R is an acyl group, and in particular is —COR^(K), whereR^(K) is a phenyl, C1-C4 alkyl, or a C1-C4 alkyl substituted with C3-C7cycloalkyl, C1-C6 alkoxy or a phenyl. In other specific embodiments, R⁷is H or C1-C4 alkyl.

In more specific embodiments, the present invention provides compoundsand salts thereof of formulas LVIV-LVVII:

orboronate protected derivatives of compounds of formulas LVIV and LVV(see BBB9-BBB11),where:BBN is as defined above;R₆₀ is an acyl group, —CO—R₆₁ where R₆₁ is H, C1-C6 alkyl, C3-C7cycloalkyl or C1-C6 alkyl substituted with C3-C7 cycloalkyl or phenyl;R₆₅ is hydrogen of C1-C4 alkyl;R₆₆ is —C1-C4 alkyl substituted with Z where Z is —OH, —NH₂, —PO(OH)₂ orpharmaceutically acceptable salts thereof, or a —COR^(Q) group whereR^(Q) is C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkyl substituted withC3-C6 cycloalkyl or phenyl, more preferably R₆₆ is —CH₂—Z, and yet morepreferably Z is —CH₂—OH; andR₇₀ is H or C1-C6 alkyl and is preferably C1-C6 alkyl, more preferablybutyl and yet more preferably —CH₂—CH₂(CH₃)₂.

Lysine sulfonamides of the forgoing formulas can be prepared, fromstarting materials and reagents that are commercially available orreadily prepared by known methods, by one of ordinary skill in the artin view of methods described in U.S. published application 20100093811,in view of methods for introducing phenyl boronate groups, benzoxaborolegeoups and borono-pyridyl groups as described herein and as are known inthe art and in view of synthetic methods that are well known in the art.Compounds herein having a boronate group protected with an N-derivatizediminodiacetic acid (see formula above) can be prepared from startingmaterials and reagents that are commercially available or readilyprepared by known methods, or routine adaptations thereof, by one ofordinary skill in the art, in view of descriptions herein and in U.S.Pat. Nos. 8,318,983, 8,557,980 and 8,722,916 as well as in references14-16.

U.S. Pat. No. 7,981,929 relates to HIV protease inhibitors having abenzofuran sulfonamide group which have structural features in commonwith darunavir. Compounds of this patent include brecanavir which hasbeen studied for the treatment of HIV infection, but which wasdiscontinued for problems in formulation. This patent is incorporated byreference herein in its entirety for the description therein of suchcompounds and salts thereof and methods of synthesizing such compounds.Compounds of this patent have structure of formula MM:

where the definitions of the formula variables are incorporated byreference herein from the patent. The patent also describes prodrugsthereof where the OH group is replaced with -OE where E is defined inthe patent. Prodrugs as described are hydrolyzed to the compound offormula MM in vivo.

The present invention includes compounds, salts and any prodrugs thereofas described therein wherein the benzofuran group linked to —SO₂— offormula MM is replaced with a phenyl boronate, a benzoxaborole or aborono-pyridyl group, particularly as in formula M-MV:

orboronate protected derivates of compounds of formula M, MI, MII or MIII,where

BBN is a phenyl boronate group, a benzoxaborole group or a boronatedpyridyl group and more specifically is selected from:

W is H or E, where E, R and R₂ are as defined in U.S. Pat. No.7,981,929. This patent is incorporated by reference herein in itsentirety for descriptions of compounds and variables therein.

In specific embodiments, R₂ is C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl,C2-C6 alkenyloxy, and C1-C6 alkyl substituted with phenyl or with aC3-C7 cycloalkyl, each of which is optionally substituted with one ormore of oxo, halo, —CF₃, C1-C3 alkoxy, —(CH₂)_(r)—[O—(CH₂)_(r)]_(s)—CH₃,where each r and s can be 0, 1, 2 or 3, where at least one r is notzero. In a more preferred embodiment R₂ is butyl and yet more preferredis isobutyl. In specific embodiments, W is H. In specific embodiments,OE is a phosphate, phosphonate or carboxylate ester. In specificembodiments E is selected from H; —PO₃(R₃₁)₂; or —PO₃R₃₁H or —PO₃H₂ orpharmaceutically acceptable salts thereof. In specific embodiments, R isa C1-C6 alkyl group, a C1-C6 alkyl group substituted with a 5-7 memberedsaturated, partially saturated or unsaturated heterocyclic group or aC1-C6 alkoxyl group substituted with a 5-7 membered saturated, partiallysaturated or unsaturated heterocyclic group, wherein the heterocyclicring has one or more heteroatom groups in the ring selected from —O—,—N═, —S—, —SO—, —SO₂—, or —N(R₅)— and/or wherein the heterocyclic ringis substituted with one to four substituents selected from C1-C3 alkyl,—CF₃, halo, C1-C3 alkoxy, or phenyl. R₅ is as defined in U.S. Pat. No.7,981,929), but R₅ is more specifically H or C1-C3 alkyl. In a specificembodiment, R is a C1-C2 alkoxy substituted with the 5-7 memberheterocyclic ring. In a more specific embodiment, R is a C1-C2 alkoxysubstituted with a 5-member heterocyclic ring as noted above having —O—,—N═, —S—, or —N(R₅)— in the ring and being optionally substituted withone or more C1-C3 alkyl groups. In a more specific embodiment R is:

In a more specific embodiment, the invention provides compounds andpharmaceutically acceptable salts of formula MV:

where BBN is a phenylboronate group, a benzoxaborole group, or aborono-pyridyl groups particularly:

or boronate protected groups there of,R₂ is butyl and particularly isobutyl. In specific embodiments, W is H.In specific embodiments, W is W where OE is a phosphate, phosphonate orcarboxylate ester. In specific embodiments E is selected from H;—PO₃(R₃₁)₂; or —PO₃R₃₁H or —PO₃H₂ or pharmaceutically acceptable saltsthereof.

Compounds, salts and any prodrugs thereof of formulas M, MI, MII, MIII,MV, and MM wherein the aryl group bonded to the sulfonamide is replacedwith the BBB group can be prepared from starting materials and reagentsthat are commercially available or readily prepared by known methods, byone of ordinary skill in the art in view of methods described in U.S.Pat. No. 7,981,929 in view of methods for introducing phenyl boronategroups, benzoxaborole groups, and borono-pyridyl groups as describedherein and as are known in the art and in view of synthetic methods thatare well known in the art. Compounds herein having a boronate groupprotected with an N-derivatized iminodiacetic acid (see formula above)can be prepared from starting materials and reagents that arecommercially available or readily prepared by known methods, or routineadaptations thereof, by one of ordinary skill in the art, in view ofdescriptions herein and in U.S. Pat. Nos. 8,318,983, 8,557,980 and8,722,916 as well as in references 14-16

More generally compounds, prodrugs, salts and esters of this inventionwhich have phenyl boronate or benzoxabrorole groups, can be preparedfrom starting materials and reagents that are commercially available orreadily prepared by known methods, by one of ordinary skill in the artin view of methods described in one or more of U.S. Pat. Nos.

U.S. Pat. Nos. 5,196,438; 5,413,999; 5,484,801; 5,484,926; 5,585,397;5,585,397; 5,744,481; 5,786,483; 5,843,946; 5,849,911; 5,852,195;5,852,195; 5,856,353; 5,914,332; 5,968,942; 6,060,476; 6,169,181;6,248,775; 6,248,775; 6,372,778; 6,417,387; 6,436,989; 6,472,407;6,500,832; 6,646,010; 6,924,286; 7,608,632; 7,981,929; 8,318, 983,8,557,980, 8,722,916 or U.S. published application 20100093811in view of methods for introducing phenyl boronates, benzoxaboroles,borono-pyridyl groups as described herein and as are known in the artand in view of synthetic methods that are well known in the art and inaddition in view of known methods for protecting boronate groups,particularly with N-substituted iminodiacetate.

The number of carbons in a given group is designated herein using theterminology CX—CY, where X and Y are integers representing the lowestnumber and the highest number of carbons in the references group, as inC1-C4 alkyl which refers to an alkyl group having 1-4 carbon atoms. In anumber of the formulas of this invention reference is made to thedefinition of variables in a given patent or patents or published U.S.patent application. In these instances, the variable definition from thepatent document listed applies. In other cases, formula variables arespecifically defined in the present specification and the definitions ofsuch variables is defined herein or employs the broadest definition inthe art of a given chemical moiety or group.

The terms alkyl or alkyl group, alone or in combination, refer to amonoradical of a straight chain or branched saturated hydrocarbon. Alkylgroups include straight-chain and branched alkyl groups. Unlessotherwise indicated alkyl groups have 1-12 carbon atoms (C1-C12 alkylgroups) and preferred are those that contain 1-6 carbon atoms (C1-C6alkyl groups) and more preferred are those that contain 1-4 carbon atoms(C1-C4 alkyl groups) and those that contain 1-3 carbon atoms (C1-C3alkyl groups). Unless otherwise indicated alkyl groups are optionallysubstituted with one or more non-hydrogen substituents as describedherein. However any alkyl group designated herein can be unsubstituted.The designation of an alkyl group having a range of carbon atomsincludes all isomers having that number of carbon atoms. Exemplary alkylgroups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, branched pentyl, n-hexyl, branched hexyl, all ofwhich are optionally substituted. Substituted alkyl groups include fullyhalogenated or semihalogenated alkyl groups, such as alkyl groups havingone or more hydrogens replaced with one or more fluorine atoms, chlorineatoms, bromine atoms and/or iodine atoms. Substituted alkyl groupsinclude fully fluorinated or semifluorinated alkyl.

The term alkoxy refers to an —O-alkyl group, where alkyl is as definedabove. Alkoxy groups include among others methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert butoxy. Alkoxygroups are optionally substituted.

The term cycloalkyl, alone or in combination, means an alkyl radicalwhich contains at least one carbon ring. These groups may be monocyclic,bicyclic or tricyclic. Unless otherwise indicated a cycloalkyl containsfrom 3 to 12 carbons and the carbon ring contains 3-10 carbons and morepreferably 3-7 carbon atoms. Examples of such cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groupsare optionally substituted.

The term alkenyl, alone or in combination, refers to a straight-chain orbranched-chain mono-,di- or poly-unsaturated aliphatic hydrocarbonradical containing the specified number of carbon atoms, or where nonumber is specified, preferably from 2-10 carbon atoms, more preferably,from 2-6 carbon atoms and also from 2-4 carbon atoms. Unlessspecifically stated, all isomers of the given number of carbon atoms areincluded. Examples of alkenyl radicals include, but are not limited to,ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- andZ-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, E,E-, E,Z-, Z,E- andZ,Z hexadienyl. Alkenyl groups are optionally substituted.

The term alkenoxy refers to an —O-alkenyl group, where alkenyl isdefined above. Alkenoxy groups are optionally substituted.

The term cycloalkenyl means an alkyl radical which contains at least onecarbon ring and at least one double bond. These groups may bemonocyclic, bicyclic or tricyclic. Unless otherwise indicated acycloalkyl contains from 3 to 12 carbons and the carbon ring contains3-10 carbons and more preferably 3-7 carbon atoms. Examples of suchcycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyland cyclooctenyl. Cycloalkenyl groups are optionally substituted.

An acyl group is an R′—CO group where R′ in general is a hydrogen, analkyl, alkenyl or alkynyl, aryl or heteroaryl group as described above.In specific embodiments, acyl groups have 1-20, 1-12, or 1-6 carbonatoms and optionally 1-3 heteroatoms, optionally one double bond or onetriple bond. In specific embodiments, R is a C1-C6 alkyl, alkenyl group.cyclic configuration or a combination thereof, attached to the parentstructure through a carbonyl functionality. Examples include acetyl,benzoyl, propionyl, isobutyryl, or oxalyl. The R′ group of acyl groupsare optionally substituted as described herein. When R′ is hydrogen, thegroup is a formyl group. An acetyl group is a CH₃—CO— group. Anotherexemplary acyl group is a benzyloxy group.

The term “aryl,” alone or in combination, refers to a carbocyclicaromatic radical (such as phenyl or naphthyl) containing the specifiednumber of carbon atoms. If not specified aryl groups contain from 6-15carbon atoms, preferably from 6-10 carbon atoms, and particularlycontain from 6-10 ring carbons. Aryl groups unless otherwise stated areoptionally substituted among others with one or more substituentsselected from alkyl, alkoxy, nitro, halogen, (for example chloro),amino, carboxylate and hydroxy. In specific embodiments, aryl group areoptionally substituted phenyl groups. Aryl groups may contain two ringsthat re fused (naphthyl) or two rings which are bonded together by a C—Cbond (biphenyl). Examples of aryl groups include, among others, phenyl,p-tolyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, indenyl, indanyl,azulenyl, fluorenyl, and anthracenyl.

The term heterocyclyl or heterocyclic refers to monoradical having aring of a specified number of ring atoms, where the ring atoms includeone or more heteroatoms (N, O, S) or heteroatom groups (e.g., —NH—, or—N(alkyl)-. More specifically, the term includes groups having a stable3-7 membered monocyclic heterocyclic ring or a 8-11 membered bicyclicheterocyclic ring. The ring can be saturated, or partially unsaturated,and which may be optionally benzofused if monocyclic and which isoptionally substituted unless otherwise stated on one or more carbonatoms by halogen, alkyl, alkoxy, oxo (═O) or on a secondary nitrogenatom by alkyl, phenyl or phenylalkyl. A number of heterocyclic groupsare exemplified in the specification. Each heterocycle consists of oneor more carbon atoms and from one to four heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur and oxidized formsthereof. Heterocycles include 5-7 membered monocyclic heterocycles and8-10 membered bicyclic heterocycles.

The term “heteroaryl” refers to a group having at least one aromaticring wherein the ring contains at least one heteroatom or heteroatomgroup, as defined above. More specifically, the term refers to stable5-6 membered monocyclic or 8-11 membered bicyclic aromatic hetero cycleswhere heterocycles is as defined above. Non-limiting examples of suchgroups include imidazolyl, quinolyl, isoquinolyl, indolyl, indazolyl,pyridazyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, quinoxolyl, pyranyl,pyrimidinyl, furyl, thienyl, triaZolyl, thiaZolyl, carbolinyl,tetrazolyl, benzofuranyl, thiamorpholinyl sulfone, oxazolyl,benzoxazolyl, benzimidazolyl, benZthiaZolyl, oxopiperidinyl,oxoppyrrolidinyl, oxoazepinyl, azepinyl, isoxazolyl, isothiazolyl,furazanyl, thiazolyl, thiadiazolyl, and oxathiolyl.

A carbocyclyl group is a group having one or more saturated orunsaturated carbon rings. Carbocyclyl groups, for example, contain oneor two double bonds. One or more carbons in a carbocyclic ring can be—CO— groups. Carbocyclyl groups include those having 3-12 carbon atoms,and optionally replacing 1 or 2 carbon atoms with a —CO— group andoptionally having 1, 2 or 3 double bonds. Carbocyclyl groups includethose having 5-6 ring carbons. Carbocyclyl groups can contain one ormore rings each of which is saturated or unsaturated. Carbocyclyl groupsinclude bicyclic and tricyclic groups. Preferred carbocyclic groups havea single 5- or 6-member ring. Carbocyclyl groups are optionallysubstituted as described herein. Specifically, carbocyclic groups can besubstituted with one or more alkyl groups. Carbocyclyl groups includeamong others cycloalkyl and cycloalkenyl groups.

Groups herein are optionally substituted most generally alky, alkenyl,and aryl, heteroaryl, and heterocyclyl groups can be substituted, forexample, with one or more oxo group, thioxo group, halogen, nitro,cyano, cyanate, azido, thiocyano, isocyano, isothiocyano, sulfhydryl,hydroxyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, aryl,aryloxy, heteroaryl, heteroaryloxy, carbocyclyl, carbocyclyloxy,heterocyclyl, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio,arylthio, thioheteroaryl, thioheteroaryl, thiocarbocyclyl,thioheterocyclyl, —COR, —COH, —OCOR, —OCOH, —CO—OR, —CO—OH, —CO—O—CO—R,—CON(R)₂, —CONHR, —CONH₂, —NR—COR, —NHCOR, —NHR, —N(R)₂, —O—SO₂—R,—SO₂—R, —SO₂—NHR, —SO₂—N(R)₂, —NR—SO₂—R, —NH—SO₂—R, —NRCO—N(R)₂,—NH—CO—NHR, —O—PO(OR)₂, —O—PO(OR)(N(R)₂), —O—PO(N(R)₂)₂, where each Rindependently is an organic group and more specifically is an alkyl,cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or heterocyclylgroup or two R within the same substitutent can together form acarbocyclic (containing only carbon ring members) or heterocyclic ringhaving 3 to 10 ring atoms. Organic groups of non-hydrogen substituentsare in turn optionally substituted with one or more halogens, nitro,cyano, isocyano, isothiocyano, hydroxyl, sulfhydryl, haloalkyl,hydroxyalkyl, amino, alkylamino, dialkylamino, arylalkyl, unsubstitutedalkyl, unsubstitued alkenyl, unsubstitued alkynyl alkylalkenyl,alkylalkynyl, haloaryl, hydroxylaryl, alkylaryl, unsubstituted aryl,unsubstituted carbocylic, halo-substituted carbocyclic,hydroxyl-substituted carbocyclic, alkyl-substituted carbocyclic,unsubstituted heterocyclic, unsubstituted heteroaryl, alkyl-substitutedheteroaryl, or alkylsubstitued heterocyclic. In specific embodiments, Rgroups of substituents are independently selected from alkyl groups,haloalkyl groups, phenyl groups, benzyl groups and halosubstitutedphenyl and benzyl groups. In specific embodiments, non-hydrogensubstituents have 1-10 carbon atoms, 1-7 carbon atoms, 1-5 carbon atomsor 1-3 carbon atoms. In specific embodiments, non-hydrogen substituentshave 1-10 heteroatoms, 1-6 heteroatoms, 1-4 heteroatoms, or 1, 2, or 3heteroatoms. Heteroatoms preferably are O, N or S.

In specific embodiments, optional substitution is substitution with 1,2, 3, 4 or 5 non-hydrogen substituents. In specific embodiments,optional substitution is substitution with 1 or 2 nonhydrogensubstituents. In specific embodiments, optional substitution issubstitution with 1 nonhydrogen substituents. In specific embodiments,optional substitution is substitution by one or more halogen, hydroxygroup, cyano group, oxo group, thioxo group, unsubstituted C1-C6 alkylgroup or unsubstituted aryl group. The term oxo group refers tosubstitution of a carbon atom with a ═O[—CO-(carbonyl)] group.

As to any of the above groups which contain one or more substituents, itis understood, that such groups do not contain any substitution orsubstitution patterns which are sterically impractical and/orsynthetically non-feasible. In addition, the compounds of this inventioninclude all stereochemical isomers arising from the substitution ofthese compounds. Compounds of the invention may contain chemical groups(acidic or basic groups) that can be in the form of salts. Exemplaryacid addition salts include acetates (such as those formed with aceticacid or trihaloacetic acid, for example, trifluoroacetic acid),adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The invention provides methods for treating or preventing HIV infectionand the symptoms and disorders associated therewith. The inventionprovides pharmaceutical compositions comprising a pharmaceuticallyeffective amount of one or more compounds and/or salts of the inventionand a pharmaceutically acceptable carrier or excipient. The compoundsand salts thereof of the invention can be used to prepare medicamentsfor the treatment and prevention of HIV infection and the symptoms anddisorders associated therewith.

The term “pharmaceutically effective amount” refers to an amounteffective in treating a virus infection, as symptom or complicationthereof, for example an HIV infection, in a patient (human or othermammal) either by administration of a single compound or salt thereof orin combination with other agents. The pharmaceutically effective amountof a given compound when administered as the only active ingredient maydiffer from its pharmaceutically effective amount when administered withother active ingredients. It will be appreciated that thepharmaceutically effective amount of a compound may differ from that ofa salt of the same compound. Treating includes the alleviation ofsymptoms of a particular disorder in a patient or a measurableimprovement of a parameter associated with a particular disorder.Treating includes treatment to prevent viral infection and to delay theprogress of an infection. The term “prophylactically effective amount”refers to an amount of a compound or salt of the invention effective inpreventing a virus infection, for example an HIV infection, in apatient. The compounds of the present invention are useful in thetreatment of individuals infected by HIV and for the prophylaxis ofthese individuals. It will be appreciated in the art, that individualsat risk for HIV infection can be treated employing one or more of thecompounds or salts of the invention to prevent or delay infection. Thecompounds and salts of present invention are useful in the treatment ofconditions associated with HIV infection, including AIDS, AIDS-relatedcomplex (ARC), progressive generalized lymphadenopathy (POL), as well aschronic CNS diseases caused by retroviruses, such as, for example HIVmediated dementia and multiple sclerosis. In general, the compounds andsalts of the invention can be employed for treatment as is known in theart for other HIV protease inhibitors as described in one or more of thepatent documents cited herein and as is known in the art.

As used herein, the term “patient” refers to a mammal, including ahuman.

Compounds of the invention may contain chemical groups (acidic or basicgroups) that can be in the form of salts. Exemplary acid addition saltsinclude acetates (such as those formed with acetic acid or trihaloaceticacid, for example, trifluoroacetic acid), adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides (formed withhydrochloric acid), hydrobromides (formed with hydrogen bromide),hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed withmaleic acid), methanesulfonates (formed with methanesulfonic acid),2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates,persulfates, 3-phenylpropionates, phosphates, picrates, pivalates,propionates, salicylates, succinates, sulfates (such as those formedwith sulfuric acid), sulfonates (such as those mentioned herein),tartrates, thiocyanates, toluenesulfonates such as tosylates,undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as benzathines, dicyclohexylamines, hydrabamines[formed with N,N-bis(dehydro-abietyl)ethylenediamine],N-methyl-Dglucamines, N-methyl-D-glucamides, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quaternized with agents such as loweralkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides,bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(e.g., benzyl and phenethyl bromides), and others.

Salts of the invention include “pharmaceutically acceptable salts” whichrefers to those salts which retain the biological effectiveness andproperties of the free bases or free acids, and which are notbiologically or otherwise undesirable. Pharmaceutically acceptable saltscomprise pharmaceutically-acceptable anions and/or cations.

Compounds of the invention can be administered in the form ofpharmaceutically acceptable salts which include the followingnon-limiting examples: alkali metal salts, such as those of lithium,potassium and sodium; alkali earth metal salts, such as those of barium,calcium and magnesium; transition metal salts, such as those of zinc;and other metal salts, such as those of aluminum, sodium hydrogenphosphate and disodium phosphate; salts of nitrates, borates,methanesulfonates, benzene sulfonates, toluenesulfonates, salts ofmineral acids, such as those of hydrochlorides, hydrobromides,hydroiodides and sulfates; salts of organic acids, such as those ofacetates, trifuoroacetates, maleates, oxalates, lactates, malates,tartrates, citrates, benzoates, salicylates, ascorbates, succinates,butyrates, valerates and fumarates, amine salts, such as those ofN,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia,diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane.

Pharmaceutically acceptable salts can be derived from inorganic ororganic acids or can be derived from inorganic or organic bases as isknown in the art.

Basic amino acids useful for salt formation include arginine, lysine andornithine. Acidic amino acids useful for slat formation include asparticacid and glutamic acid.

Compound of the invention can be administered in the form ofpharmaceutically acceptable esters which include, among others, alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl estersof acidic groups, including, but not limited to, carboxylic acids,phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids andboronic acids.

Those of ordinary skill in the art will appreciate that many organiccompounds, including salts, can form complexes with solvents in whichthey are reacted or from which they are precipitated or crystallized.These complexes are known as “solvates”. For example, a complex withwater is known as a “hydrate”. Solvates, and more particularly hydrates,of the boronated compounds of the invention are within the scope of theinvention. Pharmaceutically acceptable solvates and hydrates arecomplexes of a compound of the invention with one or more solvent orwater molecules, or 1 to about 100, or 1 to about 10, or one to about 2,3 or 4, solvent or water molecules.

Compounds and salts of the invention in the form of pharmaceuticalcompositions or dosage forms the invention can be administered by anyknown route that is appropriate for the patient being treated and forthe treatment or prophylaxis that is desired. Specificallyadministration can be orally or non-orally in the form of, for example,granules, powders, tablets, capsules, syrup, suppositories, injections,emulsions, elixir, suspensions or solutions, by mixing these effectivecomponents, individually or simultaneously, with pharmaceuticallyacceptable carriers, excipients, binders, diluents or the like.

A solid formulation for oral administration can comprise one or more ofthe compounds or salts of the invention alone or in appropriatecombination with other active ingredients. Solid formulations can be inthe form of powders, granules, tablets, pills and capsules. In thesecases, the instant compounds can be mixed with at least one additive,for example, sucrose, lactose, cellulose sugar, mannitol, maltitol,dextran, starch, agar, alginates, chitins, chitosans, pectins,tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,synthetic or semi-synthetic polymers or glycerides. These formulationscan contain, as in conventional cases, further additives, for example,an inactive diluent, a lubricant such as magnesium stearate, apreservative such as paraben or sorbic acid, an anti-oxidant such asascorbic acid, tocopherol or cysteine, a disintegrator, a binder, athickening agent, a buffer, a sweetener, flavoring agent and/or aperfuming agent. Tablets and pills can also be prepared with entericcoating. Standard methods of formulation can be applied to preparationof formulations of the compounds and salts of the invention.

Non-oral administration includes subcutaneous injection, intravenousinjection, intramuscular injections, intraperitoneal injection orinstillation. Injectable preparations, for example, sterile injectableaqueous suspensions or oil suspensions can be prepared by known methods.

The instant pharmaceutical compositions may be formulated as known inthe art for nasal aerosol or inhalation and may be prepared as solutionsin saline, and benzyl alcohol or other suitable preservatives,absorption promoters, fluorocarbons, or solubilizing or dispersingagents.

Rectal suppositories can be prepared by mixing the drug with a suitablevehicle, for example, cocoa butter and polyethylene glycol, which is inthe solid state at ordinary temperatures, in the liquid state attemperatures in intestinal tubes and melts to release the drug.

Examples of liquid preparations for oral administration includepharmaceutically acceptable emulsions, syrups, elixirs, suspensions andsolutions, which may contain an inactive diluent, for example,pharmaceutically acceptable water.

The pharmaceutical composition can be formulated for topicaladministration with a suitable ointment containing one or more of thecompounds or salts of the invention suspended or dissolved in a carrier,which include mineral oil, liquid petroleum, white petroleum, propyleneglycol, polyoxyethylene polyoxypropylene compound, emulsifying wax andpharmaceutically acceptable water. In addition, topical formulations canbe formulated with a lotion or cream containing the active compoundsuspended or dissolved in a carrier. Suitable carriers include mineraloil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol and pharmaceuticallyacceptable water.

As is understood in the art, dosages of the instant compounds aredependent on age, body weight, general health conditions, sex, diet,dose interval, administration routes, excretion rate, combinations ofdrugs and conditions of the diseases treated. While taking these andother necessary factors into consideration, generally, dosage levels ofbetween about 10 pg per day to about 5000 mg per day, preferably betweenabout 100 mg per day to about 1000 mg per day of the compound are usefulin the prevention and treatment of viral infection, including HIVinfection. Typically, the pharmaceutical compositions of this inventionwill be administered from about 1 to about 5 times per day oralternatively, as a continuous infusion. Such administration can be usedas a chronic or acute therapy. The amount of active ingredient that maybe combined with the carrier or excipient materials to produce a singledosage form will vary depending upon the patient/individual treated andthe particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (W/W). Preferably,such preparations contain from about 20% to about 80% active compound.

While these dosage ranges can be adjusted by a necessary unit base fordividing a daily dose, as described above, such doses are decideddepending on the diseases to be treated, conditions of such diseases,the age, body weight, general health conditions, sex, diet of thepatient then treated, dose intervals, administration routes, excretionrate, and combinations of drugs. While taking these and other necessaryfactors into consideration., for example, a typical preparation willcontain from about 0.05% to about 95% active compound (W/W). Preferably,such preparations contain from about 10% to about 80% active compound.The desired unit dose of the composition of this invention isadministered once or multiple times daily.

A preferred embodiment of the instant invention are compositions andformulations comprising one or more of the instant compounds incombination with one or more other HIV protease inhibitors, reversetranscriptase inhibitors, or non-nucleoside reverse transcriptaseinhibitors.

The compounds of this invention may be administered to an uninfected orHIV-infected patient either as a single agent or in combination therapywith other anti-viral agents which interfere with the replication cycleof HIV in order to increase the therapeutic effect of these compounds.

The invention relates to compositions comprising one or more compound ofthe present invention, and another antiretroviral compound as a combinedpreparation for simultaneous, separate or sequential use in treatment ofretroviral infections, in particular, in the treatment of infections.

To treat HIV infection and disease associated with HIV infections, suchas Acquired Immunodefciency Syndrome (AIDS) or AIDS Related Complex(ARC), the compounds of this invention may be co-administered incombination with, binding inhibitors, fusion inhibitors; coreceptorbinding inhibitors, RT inhibitors, nucleoside RTIs, nucleotide RTIs,NNRTIs, RNAse H inhibitors, TAT inhibitors, integrase inhibitors,protease inhibitors, such as, for example, amprenavir and fosamprenavir,ritonavir, nelfnavir, saquinavir, indinavir, lopinavir, palinavir,atazanavir, tipranavir, and/or glycosylation inhibitors.

The compounds of the present invention may also be administered incombination with immunomodulators, antibiotics, cytokines, modulators ofcytokines, chemokines or the receptors thereof or hormones to treat,ameliorate, or eliminate HIV infection and its symptoms. Suchcombination therapy in different formulations may be administeredsimultaneously, separately or sequentially. Alternatively, suchcombination may be administered as a single formulation, where theactive ingredients are released from the formulation simultaneously orseparately.

The compounds and salts of the present invention may be administered incombination, for example, with ritonavir. As used herein, a prodrug is acompound that, upon in vivo administration, is metabolized by one ormore steps or processes or otherwise converted to the biologically,pharmaceutically or therapeutically active form of the compound. Toproduce a prodrug, the pharmaceutically active compound is modified suchthat the active compound will be regenerated by metabolic processes. Theprodrug may be designed to alter the metabolic stability or thetransport characteristics of a drug, to mask side effects or toxicity,to improve the flavor of a drug or to alter other characteristics orproperties of a drug. A number of prodrugs of HIV inhibitors are knownin the art and the present description provides a description of anumber of such prodrugs.

As used herein, prodrugs include phosphonates and include compounds inwhich the boronate groups of the boronated aryl or boronated heteroarylgroup is protected with a protecting group such as that of anN-substituted iminodiacetic acid and more specifically of with theprotecting group N-methyliminodiacetic acid.

All references throughout this application, for example patent documentsincluding issued or granted patents or equivalents; patent applicationpublications; and non-patent literature documents or other sourcematerial; are hereby incorporated by reference herein in theirentireties, as though individually incorporated by reference.

All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. References cited herein are incorporated byreference herein in their entirety to indicate the state of the art, insome cases as of their filing date, and it is intended that thisinformation can be employed herein, if needed, to exclude (for example,to disclaim) specific embodiments that are in the prior art. Forexample, when a compound is claimed, it should be understood thatcompounds known in the prior art, including certain compounds disclosedin the references disclosed herein (particularly in referenced patentdocuments), are not intended to be included in the claim.

When a group of substituents is disclosed herein, it is understood thatall individual members of those groups and all subgroups, including anyisomers and enantiomers of the group members, and classes of compoundsthat can be formed using the substituents are disclosed separately.

When a compound is claimed, it should be understood that compounds knownin the art including the compounds disclosed in the references disclosedherein are not intended to be included. When a Markush group or othergrouping is used herein, all individual members of the group and allcombinations and subcombinations possible of the group are intended tobe individually included in the disclosure.

Every formulation or combination of components described or exemplifiedcan be used to practice the invention, unless otherwise stated. Specificnames of compounds are intended to be exemplary, as it is known that oneof ordinary skill in the art can name the same compounds differently.When a compound is described herein such that a particular isomer orenantiomer of the compound is not specified, for example, in a formulaor in a chemical name, that description is intended to include eachisomers and enantiomer of the compound described individual or in anycombination.

One of ordinary skill in the art will appreciate that methods, deviceelements, starting materials, and synthetic methods other than thosespecifically exemplified can be employed in the practice of theinvention without resort to undue experimentation. All art-knownfunctional equivalents, of any such methods, device elements, startingmaterials, and synthetic methods are intended to be included in thisinvention. Whenever a range is given in the specification, for example,a temperature range, a time range, or a composition range, allintermediate ranges and subranges, as well as all individual valuesincluded in the ranges given are intended to be included in thedisclosure.

As used herein, “comprising” is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps. As usedherein, “consisting of” excludes any element, step, or ingredient notspecified in the claim element. As used herein, “consisting essentiallyof” does not exclude materials or steps that do not materially affectthe basic and novel characteristics of the claim. Any recitation hereinof the term “comprising”, particularly in a description of components ofa composition or in a description of elements of a device, is understoodto encompass those compositions and methods consisting essentially ofand consisting of the recited components or elements. The inventionillustratively described herein suitably may be practiced in the absenceof any element or elements, limitation or limitations which is notspecifically disclosed herein. Without wishing to be bound by anyparticular theory, there can be discussion herein of beliefs orunderstandings of underlying principles relating to the invention. It isrecognized that regardless of the ultimate correctness of anymechanistic explanation or hypothesis, an embodiment of the inventioncan nonetheless be operative and useful.

The terms and expressions which have been employed are used as terms ofdescription and not of limitation, and there is no intention in the useof such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theinvention claimed. Thus, it should be understood that although thepresent invention has been specifically disclosed by preferredembodiments and optional features, modification and variation of theconcepts herein disclosed may be resorted to by those skilled in theart, and that such modifications and variations are considered to bewithin the scope of this invention.

THE EXAMPLES Example 1: Materials and Methods

Commercial reagents were used without further purification.(2S,3S)-1,2-epoxy-3-(boc-amino)-4-phenylbutane was from Sigma-Aldrich(St. Louis, Mo.). All glassware was oven- or flame-dried, and reactionswere performed under N₂(g) unless stated otherwise. Dichloromethane wasdried over a column of alumina. Triethylamine was dried over a column ofalumina and purified further by passage through an isocyanate scrubbingcolumn. Flash chromatography was performed with columns of 40-63 Asilica, 230-400 mesh (Silicycle, Québec City, Canada). Thin-layerchromatography (TLC) was performed on plates of EMD 250-μm silica60-F₂₅₄. The term “concentrated under reduced pressure” refers to theremoval of solvents and other volatile materials using a rotaryevaporator at water aspirator pressure (<20 torr) while maintaining thewater-bath temperature below 40° C. Residual solvent was removed fromsamples at high vacuum (<0.1 torr). The term “high vacuum” refers tovacuum achieved by a mechanical belt-drive oil pump. NMR spectra wereacquired at ambient temperature with a Bruker DMX-400 Avancespectrometer at the National Magnetic Resonance Facility at Madison(NMRFAM) and referenced to TMS or residual protic solvent. Electrosprayionization (ESI) mass spectrometry was performed with a Micromass LCT atthe Mass Spectrometry Facility in the Department of Chemistry at theUniversity of Wisconsin-Madison.

Example 2: Synthesis of B-Amprenavir (6)

A. A round-bottom flask containing 1 (synthesized as describedpreviously, [1] 1.791 g, 5.323 mmol) was dissolved in 60 mL ofdichloromethane, and the resulting solution was cooled to 0° C.Triethylamine (1.2 mL, 8.6 mmol) and 4-bromobenzenesulfonyl chloride(1.362 g, 5.330 mmol) were then added, and the reaction mixture was leftto stir overnight under an atmosphere of dry N₂(g). After 16 h, thereaction mixture was concentrated under reduced pressure, and theproduct was purified by column chromatography (silica, 30% v/v EtOAc inhexanes), resulting in 2 as a white solid (2.543 g, 86%).

¹H NMR (400 MHz, CDCl₃) δ=7.67-7.62 (m, 4H), 7.33-7.22 (m, 5H), 4.64 (d,J=8.4 Hz, 1H), 3.87-3.76 (m, 3H), 3.11 (d, J=6.1 Hz, 1H), 3.03-2.84 (m,4H), 1.91-1.81 (m, 1H), 1.36 (s, 9H), 0.91 (d, J=6.6 Hz, 3H), 0.88 (d,J=6.6 Hz, 3H); 3C NMR (100 MHz, CDCl₃) δ=156.2, 137.8, 137.7, 132.5,129.6, 128.9, 128.6, 127.9, 126.6, 79.9, 72.7, 58.4, 54.9, 53.4, 35.6,28.4, 27.2, 20.2, 20.0; HRMS (ESI) calculated for [C₂₅H₃₅BrN₂O₅SNa]⁺(M+Na⁺) requires m/z=577.1343, found 577.1364.

B. Compound 2 (0.262 g, 0.472 mmol), KOAc (0.139 g, 1.416 mmol),bis(pinacolato)diboron (0.708 g, 0.180 mmol), and Pd(dppf)Cl₂—CH₂Cl₂(34.54 mg, 0.0472 mmol) were placed in a dry Schlenk tube. The reactionflask was then evacuated and backfilled with N₂(g) five times. Freshlydegassed 1,4-dioxane (5 mL) was then added, and the reaction mixture washeated to 80° C. and stirred for 24 h under a N₂(g) atmosphere. After 24h, the reaction mixture was vacuum-filtered through a pad of Celite andconcentrated under reduced pressure, and the product was purified bycolumn chromatography (silica, 30% v/v EtOAc in hexanes), giving 3 as awhite solid (0.253 g, 89%).

¹H NMR (400 MHz, CDCl₃) δ=7.94 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.2 Hz,2H), 7.31-7.28 (m, 2H), 7.25-7.21 (m, 3H), 4.67 (d, J=8.6 Hz, 1H),3.93-3.91 (m, 1H), 3.84-3.81 (m, 1H), 3.78-3.74 (m, 1H), 3.13-3.06 (m,2H), 3.01-2.81 (m, 4H), 1.89-1.81 (m, 1H), 1.36 (s, 12H), 1.35 (s, 9H),0.89 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)δ=156.1, 140.6, 137.9, 135.5, 129.7, 128.6, 126.5, 126.4, 84.6, 79.8,72.8, 58.6, 54.9, 53.7, 35.5, 29.8, 28.4, 27.2, 25.0, 20.2, 20.0; HRMS(ESI) calculated for [C₃₁H₄₇BN₂O₇SNa]⁺ (M+Na⁺) requires m/z=624.3126,found 624.3151.

C. To a round-bottom flask containing compound 3 (0.150 g, 0.249 mmol)was added 10 mL of 4.0 M HCl in dioxane. After stirring for 4 h, thereaction mixture was purged with N₂(g) to remove excess HCl(g). Once theevolution of HCl(g) ceased, the reaction mixture was concentrated underreduced pressure and dried overnight under high vacuum. The residue wasthen dissolved in 6 mL of DCM (dichloromethane) and placed under aninert atmosphere. Triethylamine (0.17 mL, 1.2 mmol) and 4 (synthesizedas described previously, [1] 0.086 g, 0.374 mmol) were then added, andthe reaction mixture was stirred at room temperature overnight. Afterreacting for 16 h, the reaction mixture was concentrated under reducedpressure, and the product was purified by column chromatography (silica,5% v/v MeOH in), yielding 5 as a white solid (0.121 g, 79%).

¹H NMR (400 MHz, CDCl₃) δ=7.94 (d, J=7.8 Hz, 2H), 7.74 (d, J=7.8 Hz,2H), 7.32-7.28 (m, 2H), 7.25-7.21 (m, 3H), 5.12 (s, 1H), 4.85 (d, J=8.7Hz, 1H), 3.86-3.76 (m, 5H), 3.71-3.61 (m, 2H), 3.16-3.10 (m, 1H),3.01-2.86 (m, 4H), 2.83-2.78 (m, 1H), 2.13-2.05 (m, 1H), 1.96-1.88 (m,1H), 1.85-1.78 (m, 1H), 1.36 (s, 12H), 0.91 (d, J=6.6 Hz, 3H), 0.86 (d,J=6.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ=156.1, 140.4, 137.6, 135.5,129.6, 128.7, 126.7, 126.4, 84.6, 76.7, 75.5, 73.4, 72.6, 67.0, 58.8,55.2, 53.8, 35.5, 32.9, 27.3, 25.0, 20.2, 20.0; HRMS (ESI) calculatedfor [C31H₄₉BN₃O₈S]⁺ (M+NH₄ ⁺) requires m/z=633.3365, found 633.3386.

D. A round-bottom flask was charged with compound 5 (0.121 g, 0.196mmol), which was then dissolved in acetone (10 mL) and H₂O (10 mL). Theresulting solution was placed under an atmosphere of dry N₂(g), andsodium periodate (0.168 g, 0.784 mmol) and ammonium acetate (60.4 mg,0.784 mmol) were added. After stirring for 12 h, the reaction mixturewas concentrated under reduced pressure, and the product was purified bycolumn chromatography (silica, 20% v/v MeOH in DCM), giving 6 as anoff-white solid (75.42 mg, 72%). An analytically pure sample of 6 wasobtained by reverse-phase HPLC using a preparatory C18 column and alinear gradient of 10-80% v/v acetonitrile (0.1% v/v TFA) in water (0.1%v/v TFA) over 45 min. 6 eluted at 36 min and, after lyophilization, wasisolated as a white powder.

¹H NMR (400 MHz, Methanol-d₄) δ=7.80 (s, 4H), 7.27-7.22 (m, 3H),7.19-7.15 (m, 1H), 7.00 (d, J=9.4 Hz, 1H), 5.01-4.98 (m, 1H), 3.85-3.68(m, 5H), 3.47-3.43 (m, 2H), 3.15-3.08 (m, 2H), 2.98 (dd, J=15.1, 8.7 Hz,1H), 2.90 (dd, J=13.7, 6.7 Hz, 1H), 2.55 (dd, J=13.8, 10.7 Hz, 1H),2.13-1.94 (m, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H); ¹³CNMR (100 MHz, Methanol-d₄) δ=158.2, 140.1, 135.2, 135.1, 130.5, 129.2,127.4, 127.2, 76.4, 74.2, 74.1, 67.9, 58.7, 57.5, 53.8, 37.2, 33.6,28.0, 20.5, 20.4; HRMS (ESI) calculated for [C₂₈H₄₂BN₂O₉S]⁻ (M+OMe⁻)requires m/z=592.2745, found 592.2721.

Example 3: B-Darunavir (9)

A. To a round-bottom flask containing compound 3 (0.327 g, 0.543 mmol)was added 15 mL of 4.0 M HCl in dioxane. After stirring for 4 h, thereaction mixture was purged with N₂(g) to remove excess HCl(g). Once theevolution of HCl(g) ceased, the reaction mixture was concentrated underreduced pressure and dried overnight under high vacuum. The residue wasthen dissolved in 10 mL of DCM and placed under an inert atmosphere.Triethylamine (0.38 mL, 2.7 mmol) and compound 7 (synthesized asdescribed previously, [1] 0.147 g, 0.543 mmol) were then added, and thereaction mixture was stirred at room temperature overnight. Afterreacting for 16 h, the reaction was concentrated under reduced pressure,and the product was purified by column chromatography (silica, 5% v/vMeOH in DCM), yielding 8 as a white solid (0.293 g, 82%).

¹H NMR (400 MHz, CDCl₃) δ=7.94 (d, J=7.6 Hz, 2H), 7.75 (d, J=7.6 Hz,2H), 7.30-7.26 (m, 2H), 7.22-7.20 (m, 3H), 5.65 (d, J=5.1 Hz, 1H),5.04-4.99 (m, 1H), 4.95-4.92 (m, 1H), 3.96 (t, J=8.2 Hz, 1H), 3.88-3.83(m, 3H), 3.72-3.68 (m, 2H), 3.63-3.59 (1H), 3.20-3.14 (m, 1H), 3.09-3.05(m, 1H), 3.02-2.97 (m, 2H), 2.93-2.87 (m, 1H), 2.83-2.78 (m, 2H),1.87-1.79 (m, 1H), 1.49-1.43 (m, 1H), 1.36 (s, 12H), 1.26-1.24 (m, 1H),0.93 (d, J=6.5 Hz, 3H), 0.87 (d, J=6.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃)δ=155.4, 140.1, 137.5, 135.4, 129.3, 128.6, 126.6, 126.3, 109.3, 84.5,73.4, 72.7, 70.7, 69.6, 58.0, 55.1, 53.7, 45.3, 35.6, 27.3, 25.8, 24.9,24.8, 20.1, 19.8; HRMS (ESI) calculated for [C₃₃H₅₁BN₃O₉S]⁺ (M+NH₄ ⁺)requires m/z=676.3431, found 676.3440.

B. A round-bottom flask was charged with compound 8 (0.150 g, 0.228mmol), which was then dissolved in acetone (10 mL) and H₂O (10 mL). Theresulting solution was placed under an atmosphere of dry N₂(g), andsodium periodate (0.195 g, 0.911 mmol) and ammonium acetate (70.2 mg,0.911 mmol) were added. After stirring for 12 h, the reaction mixturewas concentrated under reduced pressure, and the product was purified bycolumn chromatography (silica, 20% v/v MeOH in DCM), giving rise to 9 asan off-white solid (0.113 g, 86%). An analytically pure sample of 9 wasobtained by reverse-phase HPLC using a preparatory C18 column and alinear gradient of 10-80% v/v acetonitrile (0.1% v/v TFA) in water (0.1%v/v TFA) over 45 min. Compound 9 eluted at 38 min and, afterlyophilization, was isolated as a white powder.

¹H NMR (400 MHz, Methanol-d₄) δ=7.81 (s, 4H), 7.26-7.21 (m, 4H),7.20-7.15 (m, 1H), 5.59 (d, J=5.0 Hz, 1H), 4.93 (q, J=6.4 Hz, 1H), 3.93(dd, J=9.9, 6.2 Hz, 1H), 3.84-3.65 (m, 5H), 3.46-3.43 (m, 1H), 3.21-3.10(m, 2H), 2.99-2.84 (m, 3H), 2.53 (dd, J=14.3, 10.4 Hz, 1H), 2.07-1.99(m, 1H), 1.54-1.46 (m, 1H), 1.37-1.32 (m, 1H), 0.94 (d, J=6.6 Hz, 3H),0.88 (d, J=6.6 Hz, 3H); ¹³C NMR (100 MHz, Methanol-d₄) δ=157.7, 140.3,135.2, 135.1, 130.5, 129.3, 127.4, 127.2, 110.8, 74.6, 74.5, 72.1, 70.6,58.9, 57.4, 53.9, 46.9, 37.2, 28.0, 27.0, 20.5, 20.4; HRMS (ESI)calculated for [C₃₀H₄₄BN₂O₁₀S]⁻ (M+OMe⁻) requires m/z=635.2814, found635.2821.

Example 4: Synthesis of Non-Boronated Analog Compound 11

A round-bottom flask containing compound 10 (synthesized as describedpreviously, [2]2.662 g, 7.595 mmol) was dissolved in 80 mL ofdichloromethane, and the resulting solution was cooled to 0° C.Triethylamine (3.2 mL, 22.7 mmol) and benzenesulfonyl chloride (1.476 g,8.355 mmol) were then added, and the reaction mixture was left to stirovernight under an atmosphere of dry N₂(g). After 16 h, the reactionmixture was concentrated under reduced pressure, and the product waspurified by column chromatography (silica, 30% v/v EtOAc in hexanes),resulting in 11 as a white solid (3.316 g, 89%).

¹H NMR (400 MHz, CDCl₃) δ=7.78 (d, J=7.6 Hz, 2H), 7.60 (t, J=7.6 Hz,1H), 7.52 (t, J=7.6 Hz, 2H), 7.31-7.27 (m, 2H), 7.24-7.20 (m, 3H),5.13-5.10 (m, 1H), 4.95 (d, J=8.6 Hz, 1H), 3.87-3.75 (m, 6H), 3.62 (d,J=10.5 Hz, 1H), 3.15 (dd, J=15.2, 8.3, 1H), 3.05-2.96 (m, 3H), 2.86 (td,J=14.3, 6.7 Hz, 2H), 2.12-2.05 (m, 1H), 1.95-1.89 (m, 1H), 1.85-1.80 (m,1H), 0.91 (d, J=6.6 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H); ¹³C NMR (100 MHz,CDCl₃) δ=156.2, 138.4, 137.6, 133.0, 129.6, 129.3, 128.7, 127.4, 126.7,75.5, 73.3, 72.6, 67.0, 58.8, 55.2, 53.7, 35.5, 32.9, 27.3, 20.2, 20.0;HRMS (ESI) calculated for [C₂₅H₃₈N₃O₆S]⁺ (M+NH₄ ⁺) requiresm/z=508.2476, found 508.2471.

Example 5: Synthesis of a Prodrug of Compound 6

Phosphorylation is carried out essentially as in [9] under a N₂atmosphere. Titanium tetrachloride (2 mol % with respect to compound 5)is added with stirring to THF (2 mL). Compound 5 (0.12 g, 0.2 mmol),triethylamine (0.3 mmol), THF (2 mL) diphenylchlorophosphate (0.3 mmol)and THF (2 mL) are then added to the stirred solution at roomtemperature. The reaction mixture is allowed to stir for 1 hour afterwhich water (2 mL) is added. Solvents are removed under reduced pressureand the crude intermediate is treated as described [10] in 1 MLiOH/dioxane at room temperature and at 95° C. to remove a phenyl group.The product is treated with hydrogenolysis over Adams' catalyst inEtOH/H₂O (8:2 v:v) containing a trace of AcOH followed by heating at 95C in 80% HOAc for 1 hr. The crude product is treated as in Example 2,step D to remove the boronate protecting group. The reaction mixture isconcentrated under reduced pressure, and the product is purified bycolumn chromatography (silica, 20% v/v MeOH in DCM), giving compound 12.Compound 12 is further purified by reverse-phase HPLC using apreparatory C18 column and a linear gradient of 10-80% v/v acetonitrile(0.1% v/v TFA) in water (0.1% v/v TFA), sample is collected andlyophilized.

It will be appreciated by one of ordinary skill that various means forphosphorylation of compounds 5 and/or 8 can be employed. For example,U.S. Pat. No. 6,436,989 provides methods for phosphorylation that can beemployed to form prodrugs of the compounds of this invention.

Example 6: Benzoxaborole-Substituted Amprenavir (18)

FIG. 7 provides a chemical scheme for an exemplary method for theintroduction of a benzoxaborole group into HIV protease inhibitors ofthis invention which are sulfonamide. Benzoxaborole HIV proteaseinhibitors, prodrugs, esters and salts thereof of this invention can beprepared by one of ordinary skill in the art in view of this example andwhat is well-known in the art. The synthetic methods herein can bereadily combined with those described in the patent documentsincorporated by reference herein to prepare the compounds of theinvention and prodrugs thereof, salts thereof and esters thereof.

Example 7: —Boronated Tipranavir (22)

FIGS. 8 and 9 provide exemplary methods for boronation of HIV proteaseinhibitors of this invention which are sulfonamide where a heteroarylgroup is attached to the —SO₂— group, specifically where the heteroarylgroup is a pyridyl. Tipranavir carries a pyridyl group. These methodsintroduce a —B(OH)₂ group on the pyridyl group. Formally, the resultantcompound 22 carries a

a 5-borono-pyrid-2-yl group.

HIV protease inhibitors, prodrugs, esters and salts thereof of thisinvention carrying a 5-borono-pyrid-2-yl group can be prepared by one ofordinary skill in the art in view of this example and what is well-knownin the art. The synthetic methods herein can be readily combined withthose described in the patent documents incorporated by reference hereinto prepare compounds of the invention and prodrugs thereof, saltsthereof and esters thereof wherein the sulfonamide group is:

where R can take any definition of any of the sulfonamides of theformulas herein. In specific embodiments, R is C1-C4 alkyl, C1-C4 alkylsubstituted with a C3-C7 cycloalkyl group or a phenyl group. In specificembodiments R is a butyl group or an isobutyl group.

Example 8: Preparation of an Expression Plasmid for HIV Protease

Double-stranded, linear DNA encoding HIV-1 protease withQ7K/L33I/L63I/C67A/C95A substitutions [3] and an N-terminalself-cleavable 8×His tag, and flanked by regions complementary to the T7promoter T7 terminator regions in a pET32b vector from Novagen (Madison,Wis.) was obtained from IDT (Coralville, Iowa). Linear pET32b wasprepared by PCR using primers that were the reverse-complement to thetermini of the DNA sequence encoding HIV protease. Gene and plasmidfragments were joined covalently by using Gibson assembly [4] togenerate the pET32b-HIV protease plasmid.

Example 9: Production and Purification of HIV Protease

A single colony of Escherichia coli strain BL21-CodonPlus (DE3)-RIL fromStratagene (La Jolla, Calif.) was transformed with the pET32b-HIVprotease plasmid and used to inoculate 1.00 L of Luria-Bertani mediumcontaining ampicillin (200 μM) in a Fernbach flask. The flask was shakenat 37° C. When the culture reached saturation (OD₆₀₀=2.8-3.4),expression was induced by adding IPTG (isopropylβ-D-1-thiogalactopyranoside) to 2 mM, and the flask was shaken for anadditional hour.

HIV protease was purified and folded as described previously, [5] withmodifications. Cells (typically, 3 g per liter of culture) werepelleted, resuspended in 20 mM Tris-HCl buffer, pH 7.4, containing EDTA(1 mM) with a Potter-Elvehjem homogenizer, and lysed by a single passthrough a cell disruptor from Constant Systems (Kennesaw, Ga.) at 18kPSI. Inclusion bodies were isolated by centrifugation at 20 g for 20min. The inclusion bodies were washed with the resuspension buffercontaining urea (1.0 M) and Triton X-100 (1% v/v), and again withresuspension buffer. The inclusion bodies were collected again bycentrifugation, and lyophilized.

The lyophilized inclusion bodies were dissolved in aqueous acetic acid(50% v/v) at 5 mg/mL by sonication. Unfolded HIV protease was clarifiedby centrifugation and applied to a Superdex 75 gel-filtration columnfrom General Electric (Fairfield, Conn.) that had been pre-equilibratedwith aqueous acetic acid (50%). Unfolded HIV protease, which eluted as amajor peak near the column-volume, was pooled and lyophilized. UnfoldedHIV protease (0.1 mg/mL) was folded in 100 mM sodium acetate buffer, pH5.5, containing ethylene glycol (5% v/v) and glycerol (10% v/v) at 4° C.The folded protease was clarified by centrifugation and concentrated ina stirred-cell concentrator with a 10-kDa molecular weight cutoffmembrane from EMD Millipore (Darmstadt, Germany). The concentratedsolution of HIV protease was applied again to a Superdex 75gel-filtration column that had been pre-equilibrated with foldingbuffer. A new major peak observed at ˜0.75 column-volumes was pooled andconcentrated. The folding buffer was exchanged with 1 mM sodium acetatebuffer, pH 5.0, containing NaCl (2 mM) using a PD-10 desalting columnfrom General Electric. The solution of purified HIV protease wasflash-frozen in liquid nitrogen and stored at −80° C.

Example 10: Assay of the Catalytic Activity of HIV Protease

A peptide of sequence R-E(Edans)-SGIFLETS-K(Dabcyl)-R was designed andsynthesized by Biomatik (Cambridge, Ontario, Canada). This peptide wasused as a fluorogenic substrate for HIV protease by monitoring thefluorescence of the Edans group(5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid) upon substratehydrolysis and separation from the quenching Dabcyl group(4-((4-(dimethylamino)phenyl)azo)benzoic acid, succinimidyl ester. [6]Substrate was dissolved at 1 mM by sonication in DMF containing TFA(0.1% v/v). Stock solutions of each putative HIV protease inhibitor weregenerated by dissolving the inhibitor in DMF to a concentration of 50 mMand diluting in DMF to ˜100× stocks of the final assay concentrations.Assays were performed in 50 mM sodium acetate buffer, pH 5.0, containingNaCl (100 mM). Wells in a microtiter plate were charged initially withinhibitor (various concentrations) and substrate (final concentration:10 μM). HIV protease was then added (final concentration: 50-150 pM).Reaction velocities in the assay solutions (total volume: 200 μL) weremeasured in quadruplicate at 7-9 inhibitor concentrations includingno-inhibitor and no-enzyme controls. Multiple assays were conducted inparallel with an M1000 Pro plate reader from Tecan (Maennedorf,Switzerland) in flat-black corning non-binding 96-well plate by excitingat 340 nm and monitoring fluorescence at 490 nm at ˜30-s intervals.Initial velocities were obtaining by a linear fit of the data at <10%substrate conversion after equilibration (˜5 min) using the programMicrosoft Excel from Microsoft (Redmond, Wash.). The concentration ofHIV protease was determined by active-site titration using darunavir asa titrant. Michaelis-Menten and Morrison's K_(i) analysis weredetermined with the program Prism 7 from GraphPad Software (San Diego,Calif.). Results of the assay are shown in FIG. 1 (graphs A and B, wherethe and values of K_(i) are listed in Table 1.

TABLE 1 Values of K_(i) for HIV-1 protease inhibitors. Values (± SE)were determined by non-linear regression analysis of wild-type HIV-1protease inhibition data using Morrison's equation. CompoundExperimental (pM) Literature (pM) Amprenavir 86 ± 7  100 [7] Darunavir13 ± 2   14 [8] B-Amprenavir (6) 2.1 ± 0.3 — B-Darunavir (9) 0.9 ± 0.3 —

Example 11: Inhibition of HIV Cytopathic Toxicity by B-darunavir

The ability of B-darunavir to inhibit the cytopathic toxicity of HIV wasdetermined by standard methods (11). Briefly, both human lymphocyte cellline MT-4 and plasmid pNL4-3, which directs the production of infectiousvirions (12), were obtained from the NIH AIDS Reagent Program. Prior toviral studies, the toxicity of B-darunavir for MT-4 cells was evaluated,and B-darunavir was found not to cause a significant inhibition of thegrowth of MT-4 cells at concentrations up to 1 mM. Then, MT-4 cells weretransfected with plasmid pNL4-3. Maximal virus production was detectedon Day 6 post-transfection. Viral inhibition assays were conducted with25,000 MT-4 cells in 200 μL of RPMI medium containing fetal bovine serum(10% v/v). Infections were conducted with virus at 100×TCID₅₀ byresuspending pelleted cells in 500 μL of virus-containing medium andincubating for 4 h prior to plating with B-darunavir. After 7 days, theloss of HIV cytopathic toxicity was assessed by measuring cell viabilityusing the MTS assay from Promega (Madison, Wis.). The results show thatB-darunavir at a concentration of >100 nM inhibits the toxicity of HIVfor human lymphocytes (FIG. 3).

REFERENCES

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We claim:
 1. A compound of formula:

or a salt, ester, solvate or hydrate thereof, wherein: x is 0 or 1 toshow the presence or absence of —XX—, —XX— when present is —O—, —CO—,—SO₂—, —CO—CO—, —O—CO—, —O—SO₂—, —NR₁₀—SO₂—, —NR₁₀—CO— or —NR₁₀—CO—CO—;where each R₁₀ is independently H, C1-C4 alkyl or C1-C4 alkylsubstituted with C₃-C₇ cycloalkyl; R₂₀, R_(20A) and R_(20B) areindependently selected from C₁-C₄ alkyl, C₃-C₆ cycloalkyl,C5-C6-cycloalkenyl, phenyl, C1-C4 alkyl substituted with one or morephenyl, or C3-C6 cycloalkyl groups, a C3-C6 cycloalkyl group substitutedwith or fused to phenyl or a C5-C6 cycloalkyl group substituted with orfused to a phenyl; R₂₁ is selected H; —PO₃(R₃)₂; or —PO₃R₃H or —PO₃H₂ orpharmaceutically acceptable salts thereof; or an acyl group (—CO—R₂₂),where R₂₂ is selected from C1-C4 alkyl, C2-C4 alkenyl, or C2-C10 alkylwherein one or more —CH₂— groups are replaced with —O—; or a C2-C10alkyl wherein one or more —CH₂— groups are replaced with —NH— or one ormore —CH₃ groups are replaced with —NR₂₃, where R₂₃ is H or a C1-C4alkyl; and A is selected from H; Het; C6-C10 aryl; C3-C7 cycloalkyl;C5-C7 cycloalkenyl; C1-C4 alkyl; C2-C4 alkenyl; C1-C4 alkyl substitutedwith one or more C1-C4 alkoxy, C3-C7 cycloalkyl, C5-C7 cycloalkenyl,C6-C10 aryl, or a Het group, wherein Het is selected from a 5-10membered saturated, partially saturated or unsaturated cyclic groupcontaining one or more heteroatoms or moieties selected from —N═;—N(R₂₄)—; —O—; —S—, —SO—; —SO₂—, or —CO—, where R₂₄ is selected from H,C1-C4 alkyl, C1-C4 alkyl substituted with a C3-C7 cycloalkyl group, orC1-C4 alkyl substituted with a C6-C10 aryl group; wherein each R₂₀, R₂₂,R₂₃, R₂₄, A or Het group is optionally substituted with one or more oxo,C₁-C₃-alkoxy, —OH, —C₁-C₃ alkyl, —CO—R₂₅, —N(R₂₅)₂, —CO₂R₂₅ (or when R₂₅is H, pharmaceutically acceptable salts thereof), —NR₂₅—CO—R₂₅,—CO—N(R₂₅)₂, —(CH₂)_(r)—OH (where r is 1 or 2), —CN, —NO₂, halo or —CF₃,and R₂₅ is selected from H or C₁-C₃ alkyl, and wherein BBB is aboronated aryl, boronated heteroaryl group or boronate protectedderivative thereof other than:


2. The compound, salt, ester, or solvate of claim 1, wherein BBB isselected from:


3. The compound, salt, ester, or solvate of claim 1, wherein BBB is aboronated aryl or boronated heteroaryl group wherein the boronated isprotected.
 4. The compound, salt, ester, or solvate of claim 1, whereinBBB is


5. The compound, salt, ester, or solvate of claim 1, wherein XX ispresent and is —O—, —CO—, —SO₂— or —O—CO—.
 6. The compound, salt, ester,or solvate of claim 1, wherein XX is present and is —O—CO—.
 7. Thecompound, salt, ester, or solvate of claim 1, wherein A is 5-10 memberedsaturated, partially saturated or unsaturated cyclic group containingone or more heteroatoms or moieties selected from —N═; —N(R₂₄)—; —O—;—S—, —SO—; —SO₂—, or —CO—, where R₂₄ is selected from H, C1-C4 alkyl,C1-C4 alkyl substituted with a C3-C7 cycloalkyl group, or C1-C4 alkylsubstituted with a C6-C10 aryl group.
 8. The compound, salt, ester, orsolvate of claim 1, wherein XX is present and is —O—CO—, R₂₀ is a benzylgroup R_(20A) is C1-C4 alkyl and R_(20B) is hydrogen.
 9. The compound,salt, ester, or solvate of claim 1, where R₂₁ is selected from hydrogen,—PO₃H₂, —PO₃H⁻, —PO₃ ²⁻, —CH₂—OPO₃H₂, —CH₂—OPO₃H⁻, —CH₂—OPO₃ ²⁻,—PO₃(R₃₁)₂, —PO₃R₃₁H, and pharmaceutically acceptable salts thereof,where R₃₁ is optionally substituted C1-C6 alkyl or optionallysubstituted C6-C10 aryl.
 10. The compound, salt, ester, or solvate ofclaim 1, where A is one of:


11. The compound, salt, ester, or solvate of claim 20, where A is


12. The compound of claim 1 of formula:

or a salt, ester, or solvate thereof, where R₂₁ is hydrogen, —PO₃H₂ orpharmaceutically acceptable salts thereof.
 13. The compound, salt,ester, or solvate of claim 12, wherein BBB is


14. The compound of formula:

or a salt, ester, or solvate thereof, where R₂₁ is hydrogen, —PO₃H₂ orpharmaceutically acceptable salts thereof.
 15. The compound, salt,ester, or solvate of claim 14, wherein BBB is


16. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound, salt, ester, or solvate of claim 1 and apharmaceutically acceptable carrier.
 17. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound, salt,ester, or solvate of claim 1, and a pharmaceutically acceptable carrierand further comprising ritonovir.
 18. A method for treating orpreventing HIV infection which comprises administration to a patient inneed thereof of a compound, salt, ester, or solvate of claim
 1. 19. Amethod for treating a symptom or disorder associated with HIV infectionwhich comprises administration to a patient in need thereof of acompound, salt, ester, or solvate of claim
 1. 20. A compound of formula:

or Formula:

or a salt, ester, or solvate thereof, wherein R₄₀ and R₄₅ areindependently selected from C3-C5 alkyl; C2-C6 haloalkyl; C1-C12 alkylsubstituted with halo, —N₃, phenyl, C3-C7 cycloalkyl, C5-C6cycloalkenyl, Het, —NH₂—SO₂—Het; phenyl, substituted with one or morehalo, C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, C5-C6cycloalkenyl, Het, or —NH₂—SO₂—Het; C3-C12 alkyl wherein one or more—CH₂— groups are replaced with —O— and/or one or more —CH₃ are replacedwith —OH; C2-C12 alkyl wherein one or more —CH₂— groups are replacedwith —NR₄₁— and/or one or more —CH₃ are replaced with —N(R₄₁)₂, whereR₄₁ is H or C1-C4 alkyl; C3-C12 alkyl wherein one or more —CH₂— groupsare replaced with —O— or —NR₄₁— and/or one or more —CH₃ are replacedwith —OH or —N(R₄₁)₂, where R₄₁ is H or C1-C4 alkyl; C2-C12 alkylwherein one or more —CH₂— groups are replaced with —CO— or —NR₄₁— and/orone or more —CH₃ are replaced with —N(R₄₁)₂, —OH, —COOH, or —SO₃H, whereR₄₁ is H or C1-C4 alkyl; or -Het-CO—NH—C1-C3-alkyl; R₅₀ is C1-C4 alkyl;R₅₅ is H or C1-C4 alkyl; R₆₀ is an acyl group, —CO—R₆₁ where R₆₁ is H,C1-C6 alkyl, C3-C7 cycloalkyl or C1-C6 alkyl substituted with C3-C7cycloalkyl or phenyl; R₆₅ is hydrogen of C1-C4 alkyl; R₆₆ is —C1-C4alkyl substituted with Z where Z is —OH, —NH₂, —PO(OH)₂ orpharmaceutically acceptable salts thereof, or a —COR^(Q) group whereR^(Q) is C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkyl substituted withC3-C6 cycloalkyl or phenyl, more preferably R₆₆ is —CH₂—Z, and yet morepreferably Z is —CH₂—OH; R₇₀ is H or C1-C6 alkyl and is preferably C1-C6alkyl, more preferably butyl and yet more preferably —CH₂—CH₂(CH₃)₂ andBNN is any one of: